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HYALURONIDASE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hyaluronidase is an enzyme which reduces the viscosity of the mucopolysaccharide, hyaluronic acid, and renders the tissue more readily permeable to injected fluids. Hyaluronic acid is a component of the ground substance or tissue cement of the tissue spaces.

Specific Substances

    1) Human hyaluronidase, recombinant
    2) Hyaluronidase human, recombinant
    3) CAS 9001-54-1
    4) CAS 37326-33-3
    5) Diffusing factor
    6) Invasin
    7) Spreading factor

Available Forms Sources

    A) FORMS
    1) HYALURONIDASE is available as 0.1% topical lotion and 200 Units/mL subcutaneous solution (Prod Info VITRASE(R) subcutaneous injection, 2012; Prod Info KINERASE(R) cream, lotion, 2006).
    2) HYALURONIDASE HUMAN, RECOMBINANT is available as 150 Units/mL injection solution (Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012a).
    B) USES
    1) HYALURONIDASE is indicated as an adjuvant to help increase the absorption and dispersion of other injected drugs, such as local anesthetics. It is also indicated for hypodermoclysis in adults and pediatric patients. It promotes diffusion of injected fluids and is used to facilitate subcutaneous parenteral fluid therapy. In addition, hyaluronidase is used for improvement in the resorption of radiocontrast media for urography if IV administration cannot be accomplished (Prod Info Amphadase(R) subcutaneous injection, 2012; Prod Info VITRASE(R) subcutaneous injection, 2012).
    2) HYALURONIDASE HUMAN, RECOMBINANT is indicated as an adjuvant in subQ fluid administration for achieving hydration in adults and pediatric patients. It is also used as an adjuvant to increase the dispersion and absorption of other injected or subcutaneously infused drugs. In addition, hyaluronidase human, recombinant is indicated as an adjunct in subQ urography for improving resorption of radiopaque agents (Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012)

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Hyaluronidase is indicated as an adjuvant to help increase the absorption and dispersion of other injected drugs, such as local anesthetics. Hyaluronidase is also used for improvement in the resorption of radiocontrast media for urography if IV administration cannot be accomplished.
    B) PHARMACOLOGY: Hyaluronidase is an enzyme which hydrolyzes intercellular ground substance. It enhances absorption and diffusion of drugs injected concomitantly by decreasing viscosity and barrier action of these substances. Hyaluronidase human recombinant is a purified preparation of the enzyme recombinant human hyaluronidase produced by genetically engineered Chinese Hamster Ovary cells. Hyaluronidase human recombinant is a dispersing agent which modifies connective tissue permeability through hydrolysis of hyaluronic acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Purified hyaluronidase has little toxicity. No cardiovascular, capillary, or renal effects have been reported following single large doses. Skin hypersensitivity is rare and it has low antigenicity. Nausea, vomiting, tachycardia, hypotension, dizziness, chills, urticarial reactions, local edema, and local ecchymoses may also occur during therapeutic use. Conjunctivitis, myopia, and astigmatism have occurred following subconjunctival injections of hyaluronidase. Postoperative periorbital swelling and inflammation have also been reported following periorbital injection of high concentrations of hyaluronidase.
    E) WITH POISONING/EXPOSURE
    1) Overdose of hyaluronidase has not been reported. Extensions of adverse effects seen at therapeutic doses should be expected.
    0.2.20) REPRODUCTIVE
    A) Administer hyaluronidase during pregnancy only if clearly needed. Immune globulin/recombinant human hyaluronidase combination are classified as FDA pregnancy category C by the manufacturer.

Laboratory Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    C) DECONTAMINATION
    1) Hyaluronidase is administered topically and parenterally. Hyaluronidase is a protein found in nature and is likely to be digested following an ingestion. Gastrointestinal decontamination of the topical product is generally not necessary.
    D) AIRWAY MANAGEMENT
    1) Endotracheal intubation and mechanical ventilation may be required in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None
    F) ACUTE ALLERGIC REACTION
    1) MILD to MODERATE effects: Monitor airway. Administer antihistamines with or without inhaled beta agonists, corticosteroids or epinephrine. SEVERE Effects: Administer oxygen, aggressive airway management may be necessary. Administer antihistamines, epinephrine, corticosteroids as needed. Treatment includes IV fluids and ECG monitoring.
    G) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation and treated until symptoms resolve. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite adequate treatment should be admitted.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    H) PITFALLS
    1) When managing a suspected hyaluronidase overdose, the possibility of multidrug involvement should be considered. May be difficult to distinguish hypersensitivity from local irritant effects.
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause local irritation or acute allergic reactions.
    0.4.3) INHALATION EXPOSURE
    A) INHALATION: Move patient to fresh air. Monitor for respiratory distress. If cough or difficulty breathing develops, evaluate for respiratory tract irritation, bronchitis, or pneumonitis. Administer oxygen and assist ventilation as required. Treat bronchospasm with an inhaled beta2-adrenergic agonist. Consider systemic corticosteroids in patients with significant bronchospasm.
    0.4.4) EYE EXPOSURE
    A) DECONTAMINATION: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, the patient should be seen in a healthcare facility.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) DECONTAMINATION: Remove contaminated clothing and jewelry and place them in plastic bags. Wash exposed areas with soap and water for 10 to 15 minutes with gentle sponging to avoid skin breakdown. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

    A) TOXICITY: No adverse effects were noted following intra-arterial administration of highly purified bovine hyaluronidase in a dose of 200,000 International Units in 8 mL of saline over 1 1/2 to 2 minutes into the common femoral artery for the treatment of severe peripheral arterial disease. Seven patients developed non-infectious periorbital inflammation 12 hours to 3 days after undergoing phacoemulsification under either a peribulbar or sub-tenon's block, including hyaluronidase (concentration range, 50 to 250 International Units/mL) as an adjuvant to a local anesthetic agent.
    B) THERAPEUTIC DOSES: Varies by age, weight, and clinical condition of the patient; 50 to 300 units added to the injection solution. The typical dose is 150 units of hyaluronidase added to the vehicle containing the drug. CHILDREN: HYPODERMOCLYSIS: PREMATURE INFANTS OR DURING NEONATAL PERIOD: Daily dosage should not exceed 25 mL/kg of body weight with a rate of administration no greater than 2 mL/min. INFANTS AND CHILDREN LESS THAN 3 YEARS OF AGE: limit single clysis dose to 200 mL. UROGRAPHY (SUBCUTANEOUS): Administer 75 units SubQ over each scapula. Follow each injection with a contrast medium at the same sites.

Clinical Effects

Summary Of Exposure

    A) USES: Hyaluronidase is indicated as an adjuvant to help increase the absorption and dispersion of other injected drugs, such as local anesthetics. Hyaluronidase is also used for improvement in the resorption of radiocontrast media for urography if IV administration cannot be accomplished.
    B) PHARMACOLOGY: Hyaluronidase is an enzyme which hydrolyzes intercellular ground substance. It enhances absorption and diffusion of drugs injected concomitantly by decreasing viscosity and barrier action of these substances. Hyaluronidase human recombinant is a purified preparation of the enzyme recombinant human hyaluronidase produced by genetically engineered Chinese Hamster Ovary cells. Hyaluronidase human recombinant is a dispersing agent which modifies connective tissue permeability through hydrolysis of hyaluronic acid.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) Purified hyaluronidase has little toxicity. No cardiovascular, capillary, or renal effects have been reported following single large doses. Skin hypersensitivity is rare and it has low antigenicity. Nausea, vomiting, tachycardia, hypotension, dizziness, chills, urticarial reactions, local edema, and local ecchymoses may also occur during therapeutic use. Conjunctivitis, myopia, and astigmatism have occurred following subconjunctival injections of hyaluronidase. Postoperative periorbital swelling and inflammation have also been reported following periorbital injection of high concentrations of hyaluronidase.
    E) WITH POISONING/EXPOSURE
    1) Overdose of hyaluronidase has not been reported. Extensions of adverse effects seen at therapeutic doses should be expected.

Vital Signs

    3.3.4) BLOOD PRESSURE
    A) WITH THERAPEUTIC USE
    1) HYPOTENSION has been associated with hyaluronidase toxicity during therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).
    3.3.5) PULSE
    A) WITH THERAPEUTIC USE
    1) TACHYCARDIA has been associated with hyaluronidase toxicity during therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).

Heent

    3.4.3) EYES
    A) WITH THERAPEUTIC USE
    1) CONJUNCTIVITIS
    a) Subconjunctival injections of hyaluronidase produced redness, irritation of the eyes, and myopia and astigmatism in glaucomatous patients which gradually disappeared (Stanworth, 1966).
    b) This reaction has also been reported in nonglaucomatous patients administered hyaluronidase 1500 International Units in 0.5 mL saline subconjunctivally. Maximum myopia of 3 diopters and astigmatism occurred 10 days after injection and lasted for several weeks (Treister et al, 1969).
    2) CYSTOID MACULAR EDEMA
    a) Cystoid macular edema was associated with hyaluronidase injected behind the eye prior to cataract extraction (Roper & Nisbet, 1978). Further analysis was indicated to determine a cause and effect relationship (Grant & Schuman, 1993).
    3) TEMPORARY MYOPIA
    a) A 30-year-old woman developed temporary myopia which resolved completely within 45 days of a subconjunctival injection of hyaluronidase (1500 International Units) to resolve hemorrhaging secondary to severe coughing (Singh, 1995).
    4) RETINAL DAMAGE
    a) Retinal damage occurred in rabbits after intravitreal hyaluronidase at concentrations greater than 15 International Units.
    1) Focal whitening, edema, vitreous haze, vascular abnormalities, and retinal necrosis were reported with intravitreal hyaluronidase concentrations of 30, 50, and 150 International Units (Gottlieb et al, 1990).
    b) One International Unit of intravitreal hyaluronidase produced partial vitreolysis and was nontoxic to the rabbit retina (Gottlieb et al, 1990).
    5) PERIORBITAL INFLAMMATION
    a) CASE SERIES: Seven patients developed non-infectious periorbital inflammation 12 hours to 3 days after undergoing phacoemulsification under either a peribulbar or sub-tenon's block, including hyaluronidase (concentration range, 50 to 250 International Units/mL) as an adjuvant to a local anesthetic agent. Most patients developed lid swelling and chemosis. Limitation of extraocular muscle movement and elevated intraocular pressure were observed in 3 patients. One patient had proptosis of 3 mm. All patients recovered 2 or 3 days after supportive therapy, including oral corticosteroids. Skin prick and intradermal testing of 4 patients were negative for the local anesthetic and hyaluronidase, indicating no allergic reactions to hyaluronidase. It was suggested that high concentrations of hyaluronidase may have caused the periorbital inflammation in these patients (Zamora-Alejo et al, 2013).
    6) OTHER
    a) Intravitreal injection of hyaluronidase produced formation of strands or sheets between lens and optic nerve head and iritis (Agarwal et al, 1969; Machemer & Norton, 1969).
    3.4.6) THROAT
    A) WITH THERAPEUTIC USE
    1) POSTTRAUMATIC MACROGLOSSIA
    a) CASE REPORT: A 21-year-old man developed several tongue lacerations following an injury, and was electively given hyaluronidase (1 cm (3)) for mild tongue swelling with an additional 2 cm(3) dose given 24 hours after the injury. Massive swelling of the tongue was noted within several minutes along with protrusion from the mouth. The patient required nasotracheal intubation and was treated with intravenous steroids and antibiotics with gradual resolution of symptoms over 2 days. No longterm sequelae was reported. Although no causal relationship could be determined, the author suggested that the swelling may have been related to interstitial hemorrhage or a hypersensitivity reaction to hyaluronidase (Dort, 1996).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) TACHYARRHYTHMIA
    1) WITH THERAPEUTIC USE
    a) Tachycardia has been associated with therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).
    B) VENTRICULAR FIBRILLATION
    1) WITH THERAPEUTIC USE
    a) A single case of cardiac fibrillation has been reported during therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) DIZZINESS
    1) WITH THERAPEUTIC USE
    a) Chills and dizziness are symptoms of hyaluronidase toxicity with therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) WITH THERAPEUTIC USE
    a) Nausea and vomiting have been associated with therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) URTICARIA
    1) WITH THERAPEUTIC USE
    a) Intravenous hyaluronidase was associated with urticarial reactions in 2/46 patients in one study (Laake, 1979).
    B) PURPURA
    1) WITH THERAPEUTIC USE
    a) Local ecchymoses have been reported following perineal injection (O'Leary & Erez, 1965).
    C) EDEMA
    1) WITH THERAPEUTIC USE
    a) Erythema and local edema are signs associated with hypersensitivity reaction during therapeutic use (Prod Info Hyaluronidase (Wydase(R)), 1996).
    b) Edema was reported most frequently with hypodermoclysis of hyaluronidase (Prod Info VITRASE(R) subcutaneous injection, 2012).
    c) In postmarketing evaluations, edema was reported most frequently with subcutaneous fluid administration (Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012).
    D) INJECTION SITE REACTION
    1) WITH THERAPEUTIC USE
    a) Mild local injection site reactions, such as erythema and pain, are the most commonly reported adverse event in postmarketing studies of patients who receive hyaluronidase (Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012; Prod Info VITRASE(R) subcutaneous injection, 2012).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ACUTE ALLERGIC REACTION
    1) WITH THERAPEUTIC USE
    a) Allergic reactions, such as urticaria and angioedema, were reported in less than 0.1% of patients who received hyaluronidase (Prod Info VITRASE(R) subcutaneous injection, 2012).
    B) ANGIOEDEMA
    1) WITH THERAPEUTIC USE
    a) CASE SERIES: Allergic angioedema was described in two patients following local anesthesia for dental surgery. The local anesthetic contained hyaluronidase from bull testes. Hyaluronidase-specific serum IgE antibodies were detected in both patients (Muller et al, 1986).
    C) ANAPHYLAXIS
    1) WITH THERAPEUTIC USE
    a) Hyaluronidase has been rarely associated with anaphylactic-like reactions following retrobulbar block or IV injections (Prod Info VITRASE(R) subcutaneous injection, 2012; Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012).

Reproductive

    3.20.1) SUMMARY
    A) Administer hyaluronidase during pregnancy only if clearly needed. Immune globulin/recombinant human hyaluronidase combination are classified as FDA pregnancy category C by the manufacturer.
    3.20.2) TERATOGENICITY
    A) ANIMAL STUDIES
    1) HYALURONIDASE
    a) No teratogenic effects were observed in animals administered recombinant human hyaluronidase at doses up to 28,800 times the recommended monthly human dose and no adverse fetal effects were observed at doses of 4,800 times the recommended monthly human dose. In other animal studies, no adverse effects were associated with the transfer of maternal antibodies to human recombinant hyaluronidase to the fetus in utero (Prod Info HYQVIA subcutaneous injection solution, 2014).
    b) No evidence of teratogenicity was observed with subQ recombinant human hyaluronidase (Prod Info HYLENEX(R) recombinant subcutaneous injection, 2012b).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) HYALURONIDASE: Administer hyaluronidase during pregnancy only if clearly needed (Prod Info HYDASE(TM) injection, 2015; Prod Info AMPHADASE(R) subcutaneous injection, 2014; Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    2) IMMUNE GLOBULIN/RECOMBINANT HUMAN HYALURONIDASE COMBINATION: Immune globulin/recombinant human hyaluronidase combination have been classified as FDA pregnancy category C (Prod Info AMPHADASE(R) subcutaneous injection, 2014; Prod Info Hylenex(R) recombinant subcutaneous injection, 2013; Prod Info HYQVIA subcutaneous injection solution, 2014).
    3) IMMUNE GLOBULIN/RECOMBINANT HUMAN HYALURONIDASE COMBINATION: Immune globulin/hyaluronidase should only be given to a pregnant women if clearly indicated. Women who become pregnant while taking this drug should enroll in the Hyqvia Pregnancy Registry at 1-866-424-6724 (Prod Info HYQVIA subcutaneous injection solution, 2014).
    B) LACK OF EFFECT
    1) LABOR AND DELIVERY
    a) HYALURONIDASE: When hyaluronidase was administered during labor, no complications, including increase in blood loss or differences in cervical trauma, were reported (Prod Info HYDASE(TM) injection, 2015; Prod Info AMPHADASE(R) subcutaneous injection, 2014; Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    C) ANIMAL STUDIES
    1) HYALURONIDASE
    a) Reduced fetal weight and an increased number of fetal resorptions were observed in animals administered daily doses several order of magnitude over the suggested human dose range (Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    b) Reduced fetal weight and an increased number of fetal resorptions were observed in animals. No signs of maternal toxicity were observed at doses up to 28,800 times the recommended monthly human dose and no adverse fetal effects were observed at doses of 4,800 times the recommended monthly human dose. No adverse effects were associated with the transfer of maternal antibodies to human recombinant hyaluronidase to the fetus in utero (Prod Info HYQVIA subcutaneous injection solution, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) Exercise caution when administering to a woman who is breastfeeding (Prod Info HYDASE(TM) injection, 2015; Prod Info AMPHADASE(R) subcutaneous injection, 2014; Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    B) ANIMAL STUDIES
    1) In animal studies, antibodies from the mother binding to recombinant human hyaluronidase were transferred to the nursing infant; however, the effect of these antibodies to the nursing infant are unknown (Prod Info HYQVIA subcutaneous injection solution, 2014).
    3.20.5) FERTILITY
    A) TESTICULAR DEGENERATION
    1) MALE: Testicular degeneration may occur following repeated injections of hyaluronidase, producing organ specific antibodies (Prod Info HYDASE(TM) injection, 2015; Prod Info AMPHADASE(R) subcutaneous injection, 2014).
    B) LACK OF EFFECT
    1) FEMALE: Hyaluronidase does not appear to adversely affect fertility in females. Human studies indicate that intravaginal hyaluronidase may have aided conception in sterility due to oligospermia (Prod Info HYDASE(TM) injection, 2015; Prod Info AMPHADASE(R) subcutaneous injection, 2014; Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    C) ANIMAL STUDIES
    1) HYALURONIDASE
    a) No adverse effects on sexual maturation or the ability to produce another generation of offspring were observed in animals administered daily subQ doses (Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    b) No evidence of toxicity to the male or female reproductive system (eg, semen analysis, hormone levels, menstrual cycles) was observed in animals for 39 weeks (Prod Info Hylenex(R) recombinant subcutaneous injection, 2013).
    c) Some species of animals experienced reversible infertility when immunized to produce antibodies to hyaluronidase, while other species were unaffected (Prod Info HYQVIA subcutaneous injection solution, 2014).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite adequate treatment should be admitted.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic, should be sent to a healthcare facility for evaluation and treated until symptoms resolve. Patients that remain asymptomatic can be discharged.

Monitoring

    A) No specific laboratory tests are necessary unless otherwise clinically indicated.
    B) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    C) Monitor vital signs following significant overdose.
    D) Monitor serum electrolytes in patients with significant vomiting.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Hyaluronidase is administered topically and parenterally. Hyaluronidase is a protein found in nature and is likely to be digested following an ingestion. Prehospital gastrointestinal decontamination of the topical product is generally not necessary.
    6.5.2) PREVENTION OF ABSORPTION
    A) Hyaluronidase is administered topically and parenterally. Hyaluronidase is a protein found in nature and is likely to be digested following an ingestion. Gastrointestinal decontamination of the topical product is generally not necessary.
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required.
    B) MONITORING OF PATIENT
    1) No specific laboratory tests are necessary unless otherwise clinically indicated.
    2) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    3) Monitor vital signs following significant overdose.
    4) Monitor serum electrolytes in patients with significant vomiting.
    C) ACUTE ALLERGIC REACTION
    1) Hypersensitivity reactions are rare.
    2) SUMMARY
    a) Mild to moderate allergic reactions may be treated with antihistamines with or without inhaled beta adrenergic agonists, corticosteroids or epinephrine. Treatment of severe anaphylaxis also includes oxygen supplementation, aggressive airway management, epinephrine, ECG monitoring, and IV fluids.
    3) BRONCHOSPASM
    a) ALBUTEROL
    1) ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007). CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 mg/kg (up to 10 mg) every 1 to 4 hours as needed, or 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    4) CORTICOSTEROIDS
    a) Consider systemic corticosteroids in patients with significant bronchospasm.
    b) PREDNISONE: ADULT: 40 to 80 milligrams/day. CHILD: 1 to 2 milligrams/kilogram/day (maximum 60 mg) in 1 to 2 divided doses divided twice daily (National Heart,Lung,and Blood Institute, 2007).
    5) MILD CASES
    a) DIPHENHYDRAMINE
    1) SUMMARY: Oral diphenhydramine, as well as other H1 antihistamines can be used as indicated (Lieberman et al, 2010).
    2) ADULT: 50 milligrams orally, or 10 to 50 mg intravenously at a rate not to exceed 25 mg/min or may be given by deep intramuscular injection. A total of 100 mg may be administered if needed. Maximum daily dosage is 400 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    3) CHILD: 5 mg/kg/24 hours or 150 mg/m(2)/24 hours. Divided into 4 doses, administered intravenously at a rate not exceeding 25 mg/min or by deep intramuscular injection. Maximum daily dosage is 300 mg (Prod Info diphenhydramine HCl intravenous injection solution, intramuscular injection solution, 2013).
    6) MODERATE CASES
    a) EPINEPHRINE: INJECTABLE SOLUTION: It should be administered early in patients by IM injection. Using a 1:1000 (1 mg/mL) solution of epinephrine. Initial Dose: 0.01 mg/kg intramuscularly with a maximum dose of 0.5 mg in adults and 0.3 mg in children. The dose may be repeated every 5 to 15 minutes, if no clinical improvement. Most patients respond to 1 or 2 doses (Nowak & Macias, 2014).
    7) SEVERE CASES
    a) EPINEPHRINE
    1) INTRAVENOUS BOLUS: ADULT: 1 mg intravenously as a 1:10,000 (0.1 mg/mL) solution; CHILD: 0.01 mL/kg intravenously to a maximum single dose of 1 mg given as a 1:10,000 (0.1 mg/mL) solution. It can be repeated every 3 to 5 minutes as needed. The dose can also be given by the intraosseous route if IV access cannot be established (Lieberman et al, 2015). ALTERNATIVE ROUTE: ENDOTRACHEAL ADMINISTRATION: If IV/IO access is unavailable. DOSE: ADULT: Administer 2 to 2.5 mg of 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube. CHILD: DOSE: 0.1 mg/kg to a maximum of 2.5 mg administered as a 1:1000 (1 mg/mL) solution diluted in 5 to 10 mL of sterile water via endotracheal tube (Lieberman et al, 2015).
    2) INTRAVENOUS INFUSION: Intravenous administration may be considered in patients poorly responsive to IM or SubQ epinephrine. An epinephrine infusion may be prepared by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate). CHILD: A dosage of 0.01 mg/kg (0.1 mL/kg of a 1:10,000 (0.1 mg/mL) solution up to 10 mcg/min (maximum dose 0.3 mg) is recommended for children (Lieberman et al, 2010). Careful titration of a continuous infusion of IV epinephrine, based on the severity of the reaction, along with a crystalloid infusion can be considered in the treatment of anaphylactic shock. It appears to be a reasonable alternative to IV boluses, if the patient is not in cardiac arrest (Vanden Hoek,TL,et al).
    8) AIRWAY MANAGEMENT
    a) OXYGEN: 5 to 10 liters/minute via high flow mask.
    b) INTUBATION: Perform early if any stridor or signs of airway obstruction.
    c) CRICOTHYROTOMY: Use if unable to intubate with complete airway obstruction (Vanden Hoek,TL,et al).
    d) BRONCHODILATORS are recommended for mild to severe bronchospasm.
    e) ALBUTEROL: ADULT: 2.5 to 5 milligrams in 2 to 4.5 milliliters of normal saline delivered per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 2.5 to 10 mg every 1 to 4 hours as needed, or 10 to 15 mg/hr by continuous nebulization as needed (National Heart,Lung,and Blood Institute, 2007).
    f) ALBUTEROL: CHILD: 0.15 milligram/kilogram (minimum 2.5 milligrams) per nebulizer every 20 minutes up to 3 doses. If incomplete response administer 0.15 to 0.3 milligram/kilogram (maximum 10 milligrams) every 1 to 4 hours as needed OR administer 0.5 mg/kg/hr by continuous nebulization (National Heart,Lung,and Blood Institute, 2007).
    9) MONITORING
    a) CARDIAC MONITOR: All complicated cases.
    b) IV ACCESS: Routine in all complicated cases.
    10) HYPOTENSION
    a) If hypotensive give 500 to 2000 milliliters crystalloid initially (20 milliliters/kilogram in children) and titrate to desired effect (stabilization of vital signs, mentation, urine output); adults may require up to 6 to 10 L/24 hours. Central venous or pulmonary artery pressure monitoring is recommended in patients with persistent hypotension.
    1) VASOPRESSORS: Should be used in refractory cases unresponsive to repeated doses of epinephrine and after vigorous intravenous crystalloid rehydration (Lieberman et al, 2010).
    2) DOPAMINE: Initial Dose: 2 to 20 micrograms/kilogram/minute intravenously; titrate to maintain systolic blood pressure greater than 90 mm Hg (Lieberman et al, 2010).
    11) H1 and H2 ANTIHISTAMINES
    a) SUMMARY: Antihistamines are second-line therapy and are used as supportive therapy and should not be used in place of epinephrine (Lieberman et al, 2010).
    1) DIPHENHYDRAMINE: ADULT: 25 to 50 milligrams via a slow intravenous infusion or IM. PEDIATRIC: 1 milligram/kilogram via slow intravenous infusion or IM up to 50 mg in children (Lieberman et al, 2010).
    b) RANITIDINE: ADULT: 1 mg/kg parenterally; CHILD: 12.5 to 50 mg parenterally. If the intravenous route is used, ranitidine should be infused over 10 to 15 minutes or diluted in 5% dextrose to a volume of 20 mL and injected over 5 minutes (Lieberman et al, 2010).
    c) Oral diphenhydramine, as well as other H1 antihistamines, can also be used as indicated (Lieberman et al, 2010).
    12) DYSRHYTHMIAS
    a) Dysrhythmias and cardiac dysfunction may occur primarily or iatrogenically as a result of pharmacologic treatment (epinephrine) (Vanden Hoek,TL,et al). Monitor and correct serum electrolytes, oxygenation and tissue perfusion. Treat with antiarrhythmic agents as indicated.
    13) OTHER THERAPIES
    a) There have been a few reports of patients with anaphylaxis, with or without cardiac arrest, that have responded to vasopressin therapy that did not respond to standard therapy. Although there are no randomized controlled trials, other alternative vasoactive therapies (ie, vasopressin, norepinephrine, methoxamine, and metaraminol) may be considered in patients in cardiac arrest secondary to anaphylaxis that do not respond to epinephrine (Vanden Hoek,TL,et al).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) Move patient from the toxic environment to fresh air. Monitor for respiratory distress. If cough or difficulty in breathing develops, evaluate for hypoxia, respiratory tract irritation, bronchitis, or pneumonitis.
    B) OBSERVATION: Carefully observe patients with inhalation exposure for the development of any systemic signs or symptoms and administer symptomatic treatment as necessary.
    C) INITIAL TREATMENT: Administer 100% humidified supplemental oxygen, perform endotracheal intubation and provide assisted ventilation as required. Administer inhaled beta-2 adrenergic agonists, if bronchospasm develops. Consider systemic corticosteroids in patients with significant bronchospasm (National Heart,Lung,and Blood Institute, 2007). Exposed skin and eyes should be flushed with copious amounts of water.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) DERMAL DECONTAMINATION
    1) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: No adverse effects were noted following intra-arterial administration of highly purified bovine hyaluronidase in a dose of 200,000 International Units in 8 mL of saline over 1 1/2 to 2 minutes into the common femoral artery for the treatment of severe peripheral arterial disease. Seven patients developed non-infectious periorbital inflammation 12 hours to 3 days after undergoing phacoemulsification under either a peribulbar or sub-tenon's block, including hyaluronidase (concentration range, 50 to 250 International Units/mL) as an adjuvant to a local anesthetic agent.
    B) THERAPEUTIC DOSES: Varies by age, weight, and clinical condition of the patient; 50 to 300 units added to the injection solution. The typical dose is 150 units of hyaluronidase added to the vehicle containing the drug. CHILDREN: HYPODERMOCLYSIS: PREMATURE INFANTS OR DURING NEONATAL PERIOD: Daily dosage should not exceed 25 mL/kg of body weight with a rate of administration no greater than 2 mL/min. INFANTS AND CHILDREN LESS THAN 3 YEARS OF AGE: limit single clysis dose to 200 mL. UROGRAPHY (SUBCUTANEOUS): Administer 75 units SubQ over each scapula. Follow each injection with a contrast medium at the same sites.

Therapeutic Dose

    7.2.1) ADULT
    A) ROUTE OF ADMINISTRATION
    1) ABSORPTION AND DISPERSION OF INJECTED DRUGS
    a) Varies by age, weight, and clinical condition of the patient; 50 to 300 units added to the injection solution. The typical dose is 150 units of hyaluronidase to the vehicle containing the drug (Prod Info Amphadase(R) subcutaneous injection, 2012)
    2) HYPODERMOCLYSIS
    a) 150 units of hyaluronidase will facilitate absorption of 1000 mL or more of fluid . The rate of injection, dosage, and type of solution must be individualized for each patient (Prod Info Amphadase(R) subcutaneous injection, 2012).
    3) UROGRAPHY (SUBCUTANEOUS)
    a) 75 units SubQ over each scapula. Each injection should be followed by a contrast medium at the same sites (Prod Info Amphadase(R) subcutaneous injection, 2012).
    7.2.2) PEDIATRIC
    A) DISEASE STATE
    1) HYPODERMOCLYSIS
    a) PREMATURE INFANTS OR DURING NEONATAL PERIOD: Daily dosage should not exceed 25 mL/kg of body weight with a rate of administration no greater than 2 mL/min (Prod Info Amphadase(R) subcutaneous injection, 2012).
    b) INFANTS AND CHILDREN LESS THAN 3 YEARS OF AGE: limit single clysis dose to 200 mL (Prod Info Amphadase(R) subcutaneous injection, 2012).
    2) UROGRAPHY (SUBCUTANEOUS)
    a) Administer 75 units SubQ over each scapula. Follow each injection with a contrast medium at the same sites (Prod Info Amphadase(R) subcutaneous injection, 2012).

Minimum Lethal Exposure

    A) GENERAL/SUMMARY
    1) Minimum lethal exposure has not been established.

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) No adverse effects were noted following intra-arterial administration of highly purified bovine hyaluronidase in a dose of 200,000 international units in 8 milliliters of saline over 1.5 to 2 minutes into the common femoral artery for the treatment of severe peripheral arterial disease (Odegaard, 1982).
    B) CASE SERIES: Seven patients developed non-infectious periorbital inflammation 12 hours to 3 days after undergoing phacoemulsification under either a peribulbar or sub-tenon's block, including hyaluronidase (concentration range, 50 to 250 International Units/mL) as an adjuvant to a local anesthetic agent. Most patients developed lid swelling and chemosis. Limitation of extraocular muscle movement and elevated intraocular pressure were observed in 3 patients. One patient had proptosis of 3 mm. All patients recovered 2 or 3 days after supportive therapy, including oral corticosteroids. Skin prick and intradermal testing of 4 patients were negative for the local anesthetic and hyaluronidase, indicating no allergic reactions to hyaluronidase. It was suggested that high concentrations of hyaluronidase may have caused the periorbital inflammation in these patients (Zamora-Alejo et al, 2013).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) CONCENTRATION LEVEL
    a) Toxic serum/blood concentrations have not been established.

Physicochemical

Physical Characteristics

    A) White or yellowish-white, odorless powder (JEF Reynolds , 2000)

Ph

    A) 0.3% SOLUTION: 4.5-7.5 (in water)

Molecular Weight

    A) Not available

References

General Bibliography

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    3) Dort JC: Posttraumatic macroglossia complicated by hyaluronidase injection. Otolaryngol Head Neck Surg 1996; 114:308-309.
    4) Dukes MNG: Meyler's Side Effects of Drugs, Vol 9, Exerpta Medica, New York, NY, 1980.
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    31) Product Information: KINERASE(R) cream, lotion, hyaluronidase cream, lotion. ICN Pharmaceuticals Inc, Costa Mesa, CA, 2006.
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