# OPTIVAR™

**azelastine hydrochloride ophthalmic solution, 0.05%**

## 

## Description

OPTIVAR™ (azelastine hydrochloride ophthalmic solution) 0.05% is a
sterile ophthalmic solution containing azelastine hydrochloride, a
relatively selective H~1~-receptor antagonist for topical administration
to the eyes. Azelastine hydrochloride is a white crystalline powder with
a molecular weight of 418.37. Azelastine hydrochloride is sparingly
soluble in water, methanol and propylene glycol, and slightly soluble in
ethanol, octanol and glycerine. Azelastine hydrochloride is a racemic
mixture with a melting point of 225°C. The chemical name for azelastine
hydrochloride is (±)-1-(2H)-phthalazinone,4-\[(4-chlorophenyl)
methyl\]-2-(hexahydro-1-methyl-1H-azepin-4-yl)-, monohydrochloride and
is represented by the following chemical structure:

![](media/image1.wmf)

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 benzalkonium chloride; **Inactives:**
disodium edetate dihydrate, hydroxypropylmethylcellulose, sorbitol
solution, sodium hydroxide and water for injection. It has a pH of
approximately 5.0 to 6.5 and an osmolality of approximately 271 to 312
mOsmol/L.

## Clinical Pharmacology

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

### 

### Pharmacokinetics and Metabolism

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

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

### 

### Clinical Trials

In a conjunctival antigen challenge study, OPTIVAR™ was more effective
than its vehicle in preventing itching associated with allergic
conjunctivitis. OPTIVAR™ had a rapid (within 3 minutes) onset of effect
and a duration of effect of approximately 8 hours for the prevention of
itching.

In environmental studies, adult and pediatric, patients with seasonal
allergic conjunctivitis were treated with OPTIVAR™ for two to eight
weeks. In these studies, OPTIVAR™ was more effective than its vehicle in
relieving itching associated with allergic conjunctivitis.

## INDICATIONS AND USAGE

OPTIVAR™ is indicated for the treatment of itching of the eye associated
with allergic conjunctivitis.

## 

## Contraindications

OPTIVAR™ is contraindicated in persons with known or suspected
hypersensitivity to any of its components.

## 

## Warnings

OPTIVAR™ is for ocular use only and not for injection or oral use.

## 

## Precautions

### Information for Patients:

To prevent contaminating the dropper tip and solution, care should be
taken not to touch any surface, the eyelids or surrounding areas with
the dropper tip of the bottle. Keep bottle tightly closed when not in
use. This product is sterile when packaged.

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

###  

### Carcinogenesis, Mutagenesis, Impairment of Fertility:

Azelastine hydrochloride administered orally for 24 months was not
carcinogenic in rats and mice at doses up to 30 mg/kg/day and 25
mg/kg/day, respectively. Based on a 30 µl drop size, these doses were
approximately 25,000 and 21,000 times higher than the maximum
recommended ocular human use level of 0.001 mg/kg/day for a 50 kg adult.

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

### 

### Pregnancy:

Teratogenic Effects: Pregnancy Category C. Azelastine hydrochloride has
been shown 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 ocular human use level). At an oral dose
of 30 mg/kg/day (25,000 times the recommended ocular human use level),
delayed ossification (undeveloped metacarpus), and the incidence of
14^th^ rib were increased in rats. At 68.6 mg/kg/day (57,000 times the
maximum recommended ocular human use level) azelastine hydrochloride
caused resorption and fetotoxic effects in rats. The relevance to humans
of these skeletal findings noted at only high drug exposure levels is
unknown.

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

### 

### Nursing Mothers:

It is not known whether azelastine hydrochloride is excreted in human
milk. Because many drugs are excreted in human milk, caution should be
exercised when OPTIVAR™ is administered to a nursing woman.

### 

### Pediatric Use:

Safety and effectiveness in pediatric patients below the age of 3 have
not been established.

## Geriatric Use:

No overall differences in safety or effectiveness have been observed
between elderly and younger adult patients.

## ADVERSE REACTIONS:

In controlled multiple-dose studies where patients were treated for up
to 56 days, the most frequently reported adverse reactions were
transient eye burning/stinging (approximately 30%), headaches
(approximately 15%), and bitter taste (approximately 10%). The
occurrence of these events was generally mild.

The following events were reported in 1-10% of patients: asthma,
conjunctivitis, dyspnea, eye pain, fatigue, influenza-like symptoms,
pharyngitis, pruritus, rhinitis and temporary blurring. Some of these
events were similar to the underlying disease being studied.

## 

## DOSAGE AND ADMINISTRATION

The recommended dose is one drop instilled into each affected eye twice
a day.

## HOW SUPPLIED

OPTIVAR™ (azelastine hydrochloride ophthalmic solution) 0.05% is
supplied as follows: 6 mL solution in a translucent 10 mL HDPE container
with a LDPE dropper tip, and a white HDPE screw cap.

NDC 0451-7025-06

NDC 0451-7025-00

**Storage**

Store UPRIGHT between 2° and 25°C (36° and 77°F)

### Rx only

U.S. Patent No 5164194

Marketed by:

![](media/image2.wmf)

Tewksbury, MA 01876

Issued May 2000