optivar

DESCRIPTION
OPTIVAR® (azelastine hydrochloride ophthalmic solution), 0.05% is a sterileophthalmic solution containing azelastine hydrochloride, a relatively selectiveH 1 -receptor antagonist for topical administration to the eyes optivar. Azelastinehydrochloride is a white crystalline powder with a molecular weight of 418.37 optivar. Azelastine hydrochloride is sparingly soluble in water, methanol and propyleneglycol, and slightly soluble in ethanol, octanol and glycerine optivar. Azelastine hydrochlorideis a racemic mixture with a melting point of 225°C optivar. The chemical name forazelastine hydrochloride is (±)-1-(2H)-phthalazinone,4-[(4-chlorophenyl)methyl]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride and is representedby the following chemical structure:

Empirical chemical structure: C 22 H 24 ClN 3 O·HCl

Each mL of OPTIVAR® contains: Active: 0.5 mg azelastine hydrochloride,equivalent to 0.457 mg of azelastine base; Preservative: 0.125 mg benzalkoniumchloride; Inactives: disodium edetate dihydrate, hydroxypropyl-methylcellulose,sorbitol solution, sodium hydroxide and water for injection optivar. It has a pH ofapproximately 5.0 to 6.5 and an osmolality of approximately 271 to 312 mOsmol/L optivar.

CLINICAL PHARMACOLOGY
Azelastine hydrochloride is a relatively selective histamine H 1 antagonistand an inhibitor of the release of histamine and other mediators from cells(e.g optivar. mast cells) involved in the allergic response optivar. Based on in-vitro studiesusing human cell lines, inhibition of other mediators involved in allergic reactions(e.g optivar. leukotrienes and PAF) has been demonstrated with azelastine hydrochloride optivar. Decreased chemotaxis and activation of eosinophils has also been demonstrated optivar.

Pharmacokinetics and Metabolism
Absorption of azelastine following ocular administration was relatively low optivar. A study in symptomatic patients receiving one drop of OPTIVAR® in each eyetwo to four times a day (0.06 to 0.12 mg azelastine hydrochloride) demonstratedplasma concentrations of azelastine hydrochloride to generally be between 0.02to 0.25 ng/mL after 56 days of treatment optivar. Three of nineteen patients had quantifiableamounts of N-desmethylazelastine that ranged from 0.25-0.87 ng/mL at Day 56 optivar.

Based on intravenous and oral administration, the elimination half-life, steady-statevolume of distribution and plasma clearance were 22 hours, 14.5 L/kg and 0.5L/h/kg, respectively optivar. Approximately 75% of an oral dose of radiolabeled azelastinehydrochloride was excreted in the feces with less than 10% as unchanged azelastine optivar. Azelastine hydrochloride is oxidatively metabolized to the principal metabolite,N-desmethylazelastine, by the cytochrome P450 enzyme system optivar. In-vitro studiesin human plasma indicate that the plasma protein binding of azelastine and N-desmethylazelastineare approximately 88% and 97%, respectively optivar.

Clinical Trials
In a conjunctival antigen challenge study, OPTIVAR® was more effective thanits vehicle in preventing itching associated with allergic conjunctivitis optivar. OPTIVAR®had a rapid (within 3 minutes) onset of effect and a duration of effect of approximately8 hours for the prevention of itching optivar.

In environmental studies, adult and pediatric, patients with seasonal allergicconjunctivitis were treated with OPTIVAR® for two to eight weeks optivar. In thesestudies, OPTIVAR® was more effective than its vehicle in relieving itchingassociated with allergic conjunctivitis optivar.

INDICATIONS AND USAGE
OPTIVAR® is indicated for the treatment of itching of the eye associatedwith allergic conjunctivitis optivar.

CONTRAINDICATIONS
OPTIVAR® is contraindicated in persons with known or suspected hypersensitivityto any of its components optivar.

WARNINGS
OPTIVAR® is for ocular use only and not for injection or oral use optivar.

PRECAUTIONS
Information for Patients:
To prevent contaminating the dropper tip and solution, care should be takennot to touch any surface, the eyelids or surrounding areas with the droppertip of the bottle optivar. Keep bottle tightly closed when not in use optivar. This productis sterile when packaged optivar.

Patients should be advised not to wear a contact lens if their eye is red optivar. OPTIVAR® should not be used to treat contact lens related irritation optivar. Thepreservative in OPTIVAR®, benzalkonium chloride, may be absorbed by softcontact lenses optivar. Patients who wear soft contact lenses and whose eyes are notred , should be instructed to wait at least ten minutes after instilling OPTIVAR®before they insert their contact lenses optivar.

Carcinogenesis, Mutagenesis, Impairment of Fertility:
Azelastine hydrochloride administered orally for 24 months was not carcinogenicin rats and mice at doses up to 30 mg/kg/day and 25 mg/kg/day, respectively optivar. Based on a 30 µl drop size, these doses were approximately 25,000 and21,000 times higher than the maximum recommended ocular human use level of 0.001mg/kg/day for a 50 kg adult optivar.

Azelastine hydrochloride showed no genotoxic effects in the Ames test, DNArepair test, mouse lymphoma forward mutation assay, mouse micronucleus test,or chromosomal aberration test in rat bone marrow optivar. Reproduction and fertilitystudies in rats showed no effects on male or female fertility at oral dosesof up to 25,000 times the maximum recommended ocular human use level optivar. At 68.6mg/kg/day (57,000 times the maximum recommended ocular human use level), theduration of the estrous cycle was prolonged and copulatory activity and thenumber of pregnancies were decreased optivar. The numbers of corpora lutea and implantationswere decreased; however, the implantation ratio was not affected optivar.

Pregnancy:
Teratogenic Effects: Pregnancy Category C optivar. Azelastine hydrochloride has beenshown to be embryotoxic, fetotoxic, and teratogenic (external and skeletal abnormalities)in mice at an oral dose of 68.6 mg/kg/day (57,000 times the recommended ocularhuman use level) optivar. At an oral dose of 30 mg/kg/day (25,000 times the recommendedocular human use level), delayed ossification (undeveloped metacarpus) and theincidence of 14 th rib were increased in rats optivar. At 68.6 mg/kg/day (57,000 timesthe maximum recommended ocular human use level) azelastine hydrochloride causedresorption and fetotoxic effects in rats optivar. The relevance to humans of these skeletalfindings noted at only high drug exposure levels is unknown optivar.

There are no adequate and well-controlled studies in pregnant women optivar. OPTIVAR®should be used during pregnancy only if the potential benefit justifies thepotential risk to the fetus optivar.

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