Drug Criteria & Outcomes: Hyaluronidase injection (Amphadase) formulary evaluation
Drug Criteria & Outcomes
Hyaluronidase injection (Amphadase) formulary evaluation
By Cori Williams, PharmD Candidate
Harrison School of Pharmacy
Auburn (AL) University
Hyaluronidase injection (Amphadase)-bovine (Amphastar)
• Comparable product
Hyaluronidase injection (Vitrase)-ovine (ISTA Pharmaceuticals)
NOTE: Amphadase and Vitrase are identical enzymes purified from different sources. Amphadase is purified from a bovine source, whereas Vitrase is purified from an ovine source. The current formulation of Amphadase is identical to a product called Wydase, manufactured by Wyeth-Lederle, which came on the market in 1950. Wydase has since been discontinued. A letter from the FDA dated Nov. 24, 2004, states that Amphadase is a chemical duplicate of Wydase. This document describes hyaluronidase, the chemical name for Amphadase and Wydase; therefore, all information is equally applicable to both products unless otherwise specified.
Indications
Hyaluronidase injectionbovine is FDA-approved to increase absorption and dispersion of injected drugs (particularly local anesthetics used in ophthalmic surgery), for hypodermoclysis, and for use in subcutaneous urography.1,2
Mechanism of action
Hyaluronidase hydrolyzes hyaluronic acid, a polysaccharide found in connective tissue, thereby modifying the permeability of the tissue and facilitating diffusion of other injectable drugs.3,4 Specifically, it hydrolyzes C1-C4 bonds between gluco- samine and glucuronic acid to temporarily decrease the viscosity of the cellular cement and promote diffusion of injected fluids or of localized transudates or exudates, thereby aiding their absorption.2
Pharmacokinetics1,2,4
Hyaluronidase injectionbovine is rapidly eliminated in the plasma. The complete pharmacokinetic profile is not established.
Dosage/administration1-3
- Hyaluronidase injectionbovine: injectable solution 150 units/mL in 1 mL vials.
- Hyaluronidase injection-oovine: injectable solution 200 units/mL in 1.2 mL vials; 6,200 units lyophilized powder for injection in 5 mL vials.
- Absorption and dispersion of injected drugs: 50-300 units added to the injected solution.
- Hypodermoclysis: 150-200 units will facilitate absorption of 1,000 mL or more of solution.
- Subcutaneous urography: 75 units hyaluronidase injected over each scapula followed by the injection of the contrast media at the same sites.
Preparation1,3
Lyophilized powder — Add 6.2 mL sodium chloride to the vial to obtain a final concentration of 6,200 units/mL. Further dilute to desired concentration by using reconstitution guidelines found Table 1. Use immediately after preparation.
Solution 200 units/mL or 150 units/mL — Draw the designated amount of solution from the syringe to obtain the desired hyaluronidase concentration according to Table 2.
Lyophilized powder — Store unopened vial in refrigerator at 2-8° C (35-46° F). After reconstitution, store at controlled room temperature 20-25° C (68-77° F) and use within six hours.
Solution for injection — Though each product contains an antimicrobial agent, vials are intended for single use only. Store unopened vial in refrigeration at 2-8° C (35-46° F). Protect from light. Do not freeze. It is stable at controlled room temperature for 30 days.
Special populations3
- Children (3 years of age and younger) — Hyaluronidase may be added to a small clysis (< 200 mL) or to solutions for subcutaneous injection. Check for potential chemical or physical incompatibilities.
- For premature infants, or during the neonatal period, the daily dose should not exceed 25 mL/kg of body weight and the rate of administration should not exceed 2 mL/min.
- Pregnancy Category C. Hyaluronidase has not been adequately studied in this population. Use in pregnancy only if necessary. It is not known whether hyaluronidase is excreted in breast milk. Use caution when administering to nursing mother as many drugs are excreted in the human milk.1-3
Adverse drug reactions1-3
Local injection site reactions are the most frequently reported. Edema is most commonly associated with hypodermoclysis. Urticaria and angioedema have been reported in < 0.1% of the population. Anaphylactic-like reactions following retrobulbar block or intravenous injections have occurred rarely.
Drug interactions1-3
Administration of large doses of salicylates, cortisone, corticotrophin, estrogens, or antihistamines render tissue less sensitive to hyaluronidase; therefore, it may require larger amounts of the enzyme to get an adequate dispersing effect.
When added to local anesthetic, hyaluronidase hastens analgesic onset and decreases swelling caused by local infiltration. However, increasing the spread of the local anesthetic causes increased absorption, which can increase the incidence of systemic reaction.
Precautions/Warnings1-3
Furosemide, benzodiazepines, and phenytoin are incompatible with hyaluronidase.
Consult appropriate references and observe specific precautions for other drugs administered with hyaluronidase.
- Discontinue if sensitization occurs.
- Do not use to enhance absorption of dopamine and/or alpha agonist drugs.
- Do not inject into or around acutely inflamed or infected areas.
- Do not use hyaluronidase to decrease swelling associated with bites or stings.
- Do not apply directly to cornea.
- Do not use for intravenous injections as the enzyme is rapidly inactivated in the plasma.
Contraindications
Hypersensitivity to hyaluronidase or any other ingredient in the formulation.1
Overdosage and management1-3
Symptoms of toxicity include local edema or urticaria, erythema, chills, nausea, vomiting, dizziness, tachycardia, and hypotension. Discontinue use if these occur and initiate supportive measures.
Clinical trial summary
No comparative studies exist. Several studies have evaluated the most effective concentration of hyaluronidase in ophthalmic procedures.
Trial 1: Mantovani C, et al. Efficacy of varying concentrations of hyaluronidase in peribulbar anaesthesia. Br J Anaesth 2001;86:876-878.
Purpose: To compare the quality of anesthesia obtained with 15 IU/mL of hyaluronidase to that obtained with no hyaluronidase or 150 IU/mL of hyaluronidase.
Study design: Prospective, blinded, randomized controlled trial.
Methods
- Ninety patients presenting for cataract surgery.
- Unwilling patients, those with communication or language problems, and patients with a history of allergy to local anesthetics were excluded.
- Patients received 7-10 mL of 1% ropivacaine and 2% lidocaine mixture without hyaluronidase (Group 1) or with hyaluronidase to achieve a final concentration of 15 or 150 IU/mL (Groups 2 and 3).
- Baseline eyelid and globe movements were assessed. Following injection of anesthetic superior, inferior, medial, and lateral ocular movements were assessed every two minutes. Observers also noted the time to achieve adequate anesthesia and the need for supplementary blocks.
- Outcome measures included time necessary to reach adequate anesthesia and difference in median ocular and eyelid movements.
Results
- The groups were similar in age, sex, and mean axial length of the globe.
- Mean time to adequate anesthesia was 7, 6, and 4 minutes in groups 1, 2, and 3, respectively.
- Median ocular movement scores at eight minutes were significantly lower in Group 3 than Group 1.
- No significant difference in requirements for supplementary anesthesia between the groups.
Conclusion: Hyaluronidase at a concentration of 150 IU/mL resulted in a significantly lower ocular movement score at eight minutes and was associated with a nonsignificant increase in the speed of onset of the block. Hyaluronidase may be useful in compensating for a less expert technique.
Trial 2: Kallio H, et al. Hyaluronidase as an adjuvant in bupivacaine-lidocaine mixture for retrobulbar/peribulbar block. Anesth Analg 2000;91:934-937.
Purpose: To compare the effectiveness of different concentrations of hyaluronidase added to local anesthetic solutions.
Study design: Prospective, double-blind, placebo-controlled trial.
Methods
- Seven hundred fourteen consecutive adult patients scheduled to receive retrobulbar-peribulbar block for elective cataract, glaucoma, or eye muscle surgery.
- Patients admitted for emergency surgery, corneal transplantation, retinal ablation, or vitreous operations were excluded.
- Patients were randomized to receive a local anesthetic injection, 1:1 mixture of 0.75% bupivacaine and 2% lidocaine with 5 mcg/mL epinephrine, containing no hyaluronidase, 3.75 IU/mL hyaluronidase, or 7.5 IU/mL hyaluronidase.
- Movement of the six extraocular muscles, levator palpebrae muscle, and orbicularis oculi muscle was assessed 10 minutes after anesthetic injection.
- The need for supplementary block or general anesthesia was noted.
Results
- Demographic data were similar.
- Initial block was adequate significantly more often in the groups given hyaluronidase.
- No significant difference in quality of anesthetic block was found.
- Eye muscle movements were similar in both groups given hyaluronidase and were found to be abolished more often than in the group not given hyaluronidase.
Conclusion: The addition of 3.75 IU/mL adequately improves the retrobulbar/peribulbar block. Doubling the concentration offers no further advantage.
Trial 3: Dempsey GA, et al. Hyaluronidase and peribulbar block. Br J Anaesth 1997;78:671-674.
Purpose: To assess the effect of two concentrations of hyaluronidase on quality of peribulbar block.
Study design: Prospective, blinded, randomized controlled trial.
Methods: Two hundred patients undergoing elective intraocular surgery were randomized
to receive a 1:1 mixture of 0.5% bupivacaine and 2% lignocaine without hyaluronidase (Group 1), with hyaluronidase 50 IU/mL (Group 2), or with hyaluronidase 300 IU/mL (Group 3).
Ocular movements were assessed at one-, five-, and 10-minute intervals.
Results
- No significant differences in age, sex, or disease status.
- Incidence of successful blocks at five minutes was significantly greater in both groups with hyaluronidase compared to control.
- No significant difference was found between the different concentrations of hyaluronidase.
Conclusion: Hyaluronidase 300 IU/mL and 50 IU/mL improved the quality of peribulbar block at five minutes. Hyaluronidase 300 UI/mL is safe and effective for use in peribulbar blocks.
Trial 4: DeBroff BM, et al. Retrobulbar anesthesia with 7.5 vs. 0.75 IU/mL hyaluronidase. Can J Opthalmol 1995;30:262-264.
Purpose: To determine whether there is a difference in time to akinesia, amount of conjunctival chemosis, and need for supplemental injection between local anesthetic injections with 7.5 or 0.75 IU/mL hyaluronidase.
Study design: Prospective, randomized, double-blind clinical trial.
Methods
- Thirty-seven patients scheduled to undergo successive bilateral cataract extraction procedures.
- Patients who had undergone previous surgery in either eye and those with a previous history of orbital trauma were excluded.
- The two concentrations of hyaluronidase were administered to the two eyes of the same patient.
- Investigators used a 1:1 mixture of 4% lidocaine and 0.75% bupivacaine with 1:200,000 epinephrine containing either 0.75 or 7.5 IU/mL.
- Globe akinesia was assessed every minute for the first five minutes, then at seven, 10, 15, and 20 minutes after retrobulbar injection.
- Levator akinesia was assessed at one, two, three, four, five, seven, 10, 15, 20, 30, and 40 minutes following retrobulbar injection.
- The amount of conjunctival chemosis was assessed immediately following retrobulbar injection and again just before peribulbar injection, about five minutes later.
Results
- No significant correlation between hyaluronidase concentration and the need for a supplemental injection.
- Mean globe akinesia score was significantly higher with the higher concentration of hyaluronidase at one and two minutes.
- No significant difference was noted in mean chemosis scores.
Conclusion: Assuming proper placement of the needle during retrobulbar injection, beneficial effects of hyaluronidase may be obtained with lower dosages than those currently utilized.
Limitations: The investigators used double the concentration of lidocaine compared to other studies.
Formulary recommendation
The cost per unit is comparable for all products. There are no serious side effects associated with any of the individual products or formulations. Use of the lyophilized powder is not recommended due to the increased preparation time and the six-hour shelf-life after reconstitution.
Preparation time is similar for each of the solutions. It is recommended that hyaluronidase injection-bovine be centrally stocked. Use of hyaluronidase injection-ovine would be warranted if a patient has a documented allergy to bovine proteins.
References
- Amphastar Pharmaceuticals Amphadase [package insert]. Rancho Cucamonga, CA; January 2005. Accessed on Aug. 4, 2005.
- ISTA Pharmaceuticals. Vitrase® [package insert]. Irvine, CA.
- Killion K, ed. Drug Facts and Comparisons. Loose leaf edition. St. Louis: Facts and Comparisons; May 2005:1120c-d.
- Menzel EJ, Farr C. Hyaluronidase and its substrate hyaluronon: Biochemistry, biological activities, and therapeutic uses. Cancer Letters 1998;131:3-11.
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