VA Class:OP900
ATC Class:S03AA07
Emedastine difumarate, a benzimidazole derivative, is a histamine H1-receptor antagonist.1, 12
Emedastine difumarate ophthalmic solution is used for the symptomatic relief of allergic conjunctivitis.1 This indication is based on a 6-week environmental study in which therapy with the drug was shown to be effective in the relief of the signs and symptoms (e.g., ocular itching, redness, chemosis, swelling) associated with this condition.1, 12, 14, 15 Results of several studies indicate that in healthy individuals who were challenged with conjunctival antigen initially and 4 hours after receiving topical emedastine or vehicle, emedastine was more effective than vehicle in providing relief of ocular itching associated with allergic conjunctivitis.1, 12, 14
Avoidance of allergen and other triggering factors (e.g., irritants) and application of cold compresses and lubricating eye drops are the initial means of managing allergic conjunctivitis.6, 7, 8, 9, 10, 11 Drug therapy generally is reserved for use when such avoidance is not possible or is ineffective, and can include both prophylactic (e.g., topical mast-cell stabilizers) and symptomatic (e.g., topical and/or systemic antihistamines, topical vasoconstrictors, topical steroidal and nonsteroidal anti-inflammatory agents [NSAIAs]) therapy.6, 7, 8, 9, 10, 11 The specific therapy(ies) employed will depend on the characteristics and severity of the allergic conjunctivitis.6, 7, 8, 9, 10, 11 For patients with seasonal allergic conjunctivitis, prophylaxis with a mast-cell stabilizer often is initiated before and maintained throughout the pollen season, and symptomatic therapy with other agents (e.g., topical antihistamines, topical NSAIAs) generally is initiated as necessary to provide acute relief.6, 7, 8, 9, 10 Topical corticosteroids usually are reserved for short-term use in patients with moderate to severe symptoms of allergic conjunctivitis.6, 7, 8, 9
Emedastine difumarate is applied topically to the eye as an ophthalmic solution.1 The manufacturer warns that commercially available emedastine difumarate ophthalmic solution is not for injection or oral use .1 Care should be taken to avoid contamination of the solution container.1 (See Cautions: Precautions and Contraindications.)
Emedastine difumarate ophthalmic solution contains benzalkonium chloride, which may be absorbed by some soft contact lenses.1 Contact lenses should be removed prior to administration of each dose of emedastine difumarate ophthalmic solution. Patients whose eyes are not red may reinsert soft contact lenses 10 minutes after administration of the ophthalmic solution.1
When more than one topical ophthalmic drug is used in a patient receiving emedastine difumarate ophthalmic solution, the drugs should be administered at least 5 minutes apart.12
Dosage of emedastine difumarate is expressed in terms of emedastine.1
For the symptomatic relief of allergic conjunctivitis in adults and children 3 years of age or older, the usual dosage of emedastine is 1 drop of a 0.05% solution in the affected eye(s) up to 4 times daily.1
Emedastine difumarate ophthalmic solution generally is well tolerated following topical application to the eye.1, 12, 14 Safety of ophthalmic emedastine has been evaluated in placebo-controlled and comparative clinical studies of 42 days' duration.1, 12 The most frequently reported adverse effect with ophthalmic use was headache.1
Blurred vision,1 ocular burning or stinging,1 corneal infiltrates,1 corneal staining,1 ocular discomfort,1 dry eye,1 foreign body sensation,1 ocular hyperemia,1 keratitis,1 ocular pruritus,1 or tearing1 was reported in less than 5% of patients receiving emedastine difumarate ophthalmic solution in clinical studies.1 Some of these adverse effects were considered to be related to the underlying disease, and a causal relationship to the drug has not been established.1, 12
Emedastine difumarate appears to have a low potential for causing adverse systemic effects when applied topically to the eye.1, 12, 14 Headache occurred in 11% of patients receiving ophthalmic emedastine in clinical studies.1 Other adverse effects that have been reported in less than 5% of patients receiving topical emedastine to the eye in clinical studies include abnormal dreams,1 asthenia,1 bad taste,1 dermatitis,1 rhinitis,1 and sinusitis.1
Precautions and Contraindications
The manufacturer states that emedastine difumarate ophthalmic solution should not be used for the symptomatic management of contact lens-related irritation.1 Patients should be advised not to wear contact lenses if their eye(s) are red.1 In addition, patients should be warned to remove their soft contact lenses prior to administration of each dose of emedastine difumarate ophthalmic solution because the solution contains benzalkonium chloride, which may be absorbed by some soft contact lenses.1 Patients whose eyes are not red may reinsert soft contact lenses 10 minutes after administration of the ophthalmic solution.1
Patients should be informed that improper handling of ocular solutions can result in contamination of the solution by common bacteria known to cause ocular infections and that they should avoid allowing the tip of the dispensing container to contact the eye, eyelids, or surrounding structures.1, 12 The dropper bottle should be closed tightly when not in use.1 The manufacturer states that emedastine difumarate ophthalmic solution should not be used if the solution is discolored.1
Emedastine difumarate ophthalmic solution is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.1
Safety and efficacy of emedastine ophthalmic solution in children younger than 3 years of age have not been established.1
Emedastine ophthalmic solution appears to be well tolerated in children as young as 3 years of age.13, 14 In one study, the adverse effect profile in children 3-16 years of age receiving topical emedastine to the eye up to 4 times daily for 42 days was similar to that in children receiving placebo.14 In addition, the adverse effect profile in ophthalmic emedastine-treated children 3-16 years of age was similar to that in individuals 17 years of age or older.14
Safety and efficacy of emedastine ophthalmic solution in patients 65 years of age or older are similar to those in younger patients.1
Mutagenicity and Carcinogenicity
Emedastine difumarate was not mutagenic in the in vitro bacterial reverse mutation (Ames) test, a modified Ames test, the in vitro mammalian chromosome aberration test, the in vitro mammalian forward mutation test, the in vitro mammalian DNA repair synthesis test, the in vivo mammalian sister chromatid exchange test, or the in vivo mouse micronucleus test.1
There was no evidence of carcinogenicity in lifetime studies in mice or rats receiving oral emedastine dosages exceeding 80,000 or 26,000 times, respectively, the maximum recommended human ocular dosage of 0.002 mg/kg daily for a 50-kg adult.1 Higher emedastine dosages have not been evaluated.1
Pregnancy, Fertility, and Lactation
Reproduction studies in rats and rabbits receiving oral emedastine dosages 15,000 times the maximum recommended human ocular dosage did not reveal evidence of teratogenicity.1 While no effects on perinatal or postnatal development were observed in rats receiving emedastine dosages 15,000 times the maximum recommended human ocular dosage, an increased incidence of external, visceral, and skeletal anomalies was observed in offspring of rats receiving emedastine dosages 70,000 times the maximum recommended human ocular dosage.1 There are no adequate and well-controlled studies to date using emedastine in pregnant women, and the drug should be used during pregnancy only when clearly needed.1
Reproduction studies in rats receiving emedastine dosages 15,000 times the maximum recommended human ocular dosage have not revealed evidence of impaired fertility or effects on reproductive performance.1
It is not known whether emedastine is distributed into human milk following topical application to the eye; however, the drug is distributed into milk in rats following oral administration.1 Therefore, emedastine should be used with caution in nursing women.1
Specific drug interaction studies involving emedastine difumarate ophthalmic solution and other drugs have not been conducted to date.12
The manufacturer states that overdosage following oral ingestion of the commercially available ophthalmic solution is unlikely given the limited amount (0.5 mg/mL) of emedastine present in the solution and volume (5 mL) in the container.1, 12 Somnolence and malaise have been reported in healthy individuals receiving oral emedastine 2-4 mg daily.1, 12
The oral LD50 in guinea pigs is 744 mg/kg.5 The LD50 of the drug following oral, IV, or subcutaneous administration in mice and rats and after oral administration in dogs exceeds 14,000 times the maximum recommended ocular human use levels.14
In case of emedastine overdosage, the manufacturer states that supportive and symptomatic treatment should be initiated.1
Emedastine is a relatively selective histamine H1-receptor antagonist.1, 2, 3, 14 In vitro studies indicate that emedastine has high affinity for H1 receptors (Ki of 1.3 nmol/L) and considerably weaker affinity for H2 (Ki of 49,067 nmol/L) and H3 receptors (Ki of 12,430 nmol/L).1, 3, 14 Emedastine has little or no affinity for adrenergic, cholinergic, dopaminergic, prostanoid, or serotonergic receptors.1, 2, 3, 14
In one animal study, ophthalmic administration of emedastine (0.0001-1%) 1 minute to 8 hours prior to subconjunctival injection of histamine inhibited the conjunctival vascular permeability response in a concentration-dependent manner.1, 2 In addition, the effect of topical emedastine on vascular permeability appears to be receptor-specific because ophthalmic solutions of emedastine 0.1% failed to substantially attenuate changes in conjunctival vascular permeability induced by serotonin or platelet-activating factor (PAF).1, 2 Emedastine does not appear to have local anesthetic activity4 or to affect pupillary size.14
In animals, the potency of emedastine difumarate (as measured by inhibition of histamine-induced increases in conjunctival vascular permeability) was about 100, 357, or 5813 times that of levocabastine, pheniramine, or antazoline, respectively, on a molar basis.2, 14
The likelihood of systemic effects appears to be minimal following topical application of emedastine.1 (See Cautions: Systemic Effects.)
The extent of ocular and systemic absorption of emedastine difumarate following topical application to the eye in humans has not been fully elucidated; however, only limited concentrations appear to be achieved systemically following such application.1 Following topical application to the eyes of 2 drops (60 µL) of a 0.05% solution of emedastine twice daily for 15 days in a limited number of healthy adults, plasma concentrations usually were undetectable (detection limit of 0.3 ng/mL).1, 12 However, detectable plasma concentrations (range: 0.3-0.49 ng/mL) were present in 40% of patients.1, 12
Results of histamine challenge studies indicate that emedastine has a rapid onset and long duration of action following ocular administration of the drug.2, 14
Distribution of emedastine difumarate into human ocular tissues and fluids has not been characterized.12
Following oral administration of emedastine, the plasma elimination half-life of the drug is about 3-4 hours.1
Following oral administration of emedastine, the drug is metabolized in the liver principally to 5- and 6-hydroxyemedastine, metabolites that appear to undergo further oxidation to form 5'-oxo analogs.1, 12 Emedastine N -oxide also is formed as a minor metabolite.1, 12
In adults, about 44% of an oral dose is recovered in the urine within 24 hours.1 About 3.6% of an orally administered dose is excreted in urine as parent drug; 5- and 6-hydroxyemedastine and their conjugates also are recovered in urine.1
Emedastine difumarate, a benzimidazole derivative, is a histamine H1-receptor antagonist.1, 12 The drug is structurally unrelated to other currently available antihistamines.1, 12
Emedastine difumarate occurs as a fine, white, crystalline powder and has solubilities of 229 mg/mL in water and 17 mg/mL in alcohol at room temperature.1, 12 The drug has pKas of 4.51 and 8.48.12
Emedastine difumarate ophthalmic solution is a sterile, isotonic solution of the drug in purified water; hydrochloric acid and/or sodium hydroxide may be added to adjust pH to approximately 7.4.1, 12 The commercially available ophthalmic solution is a clear, colorless solution and also contains benzalkonium chloride as a preservative, sodium chloride to adjust tonicity, hydroxypropyl methylcellulose, and tromethamine and has an osmolality of approximately 300 mOsm/kg.1, 12
Emedastine difumarate ophthalmic solution should be stored at 4-30°C.1 When stored as directed, the commercially available ophthalmic solution has an expiration date of 24 months following the date of manufacture.12 Discolored solutions should be discarded.1
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
AHFS® Drug Information. © Copyright, 1959-2022, Selected Revisions January 1, 2009. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, MD 20814.
1. Alcon Laboratories Inc. Emadine® (emedastine difumarate) ophthalmic solution 0.05% prescribing information. Forth Worth, TX; 2003 Aug.
2. Yanni JM, Stephens DJ, Parnell DW et al. Preclinical efficacy of emedastine, a potent, selective histamine H1 antagonist for topical ocular use. J Ocular Pharmacol . 1994; 10:665-75.
3. Sharif NA, Su SX, Yanni JM. Emedastine: a potent, high affinity histamine H1 receptor-selective antagonist for ocular use: receptor binding and second messenger studies. J Ocular Pharmacol . 1994; 10:653-64.
4. Fukuda T, Saito T, Yoshidomi M et al. Influence of 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole difumarate (KB-2413), a new antiallergic, on ciliary movement. Arzneimittelforschung . 1984; 34:816-8. [PubMed 6149756]
5. Budavari S, O'Neil MJ, Smith A et al, eds. The Merck index. 12th ed. Rahway, NJ: Merck & Co, Inc; 1996:601.
6. Ciprandi G, Buscaglia S, Cerqueti PM et al. Drug treatment of allergic conjunctivitis: a review of the evidence. Drugs . 1992; 43:154-76. [PubMed 1372215]
7. Morrow GL, Abbott RL. Conjunctivitis. Am Fam Physician . 1998; 57:735-46. [PubMed 9490996]
8. Titi MJ. A critical look at ocular allergy drugs. Am Fam Physician . 1996; 53:2637-42. [PubMed 8644576]
9. Galindez OA, Kaufman HE. Coping with the itchy-burnies: the management of allergic conjunctivitis. Ophthalmology . 1996; 103:1335-6. [PubMed 8841290]
10. Friedlaender MH. Current concepts in ocular allergy. Ann Allergy . 1991; 67:5-10,13. [PubMed 1859041]
11. Trocme SD. Medical therapy for ocular allergy. Mayo Clin Proc . 1992; 67:557-65. [PubMed 1359206]
12. Alcon Laboratories; Fort Worth, TX: Personal communication.
13. Reviewers' comments (personal observations).
14. Alcon Laboratories. Emadine® (emedastine difumarate) ophthalmic solution 0.05% product monograph. Fort Worth, TX: (not dated).
15. Verin P, Secchi A, Easty DL et al. Efficacy and safety of emedastine eye drops 0.05% compared to levocabastine eye drops 0.05% in allergic conjunctivitis. Invest Ophthalmol Vis Sci . 1998; 39:S549.