OPTIVAR® azelastine hydrochloride ophthalmic solution, 0.05%

OPTIVAR - azelastine hydrochloride solution/ drops 
Meda Pharmaceuticals Inc.

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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 H1-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:

Chemical Structure of Azelastine Hydrochloride

Empirical chemical structure: C22H24ClN3O•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, hypromellose, sorbitol solution, sodium hydroxide and water for injection. It has a pH of approximately 5.0 to 6.5 and an osmolarity of approximately 271 to 312 mOsmol/L.

CLINICAL PHARMACOLOGY:

Azelastine hydrochloride is a relatively selective histamine H1 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 of 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 or single-use container. Keep bottle tightly closed when not in use. Discard single-use container immediately after 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 14th 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:
OPTIVAR® 6 mL (NDC#0037-7025-60) solution in a translucent 10 mL HDPE container with a LDPE dropper tip and a white HDPE screw cap.
OPTIVAR® 0.2 mL (NDC#0037-7025-01) solution in a translucent 1 mL HDPE single-use container, packaged as 4 single-use containers in a foil pouch in a carton. The 0.2 mL foil pouch will be distributed as a professional sample only.

Attention:

Once OPTIVAR® 0.2 mL unit dose foil pouch is open, unopened containers can be used for one month, not to exceed the expiration date imprinted on the container. After one month they should be discarded. Use only if foil pouch is sealed and single container is intact. Discard each container immediately after use.

Storage

OPTIVAR® 6 mL container: Store UPRIGHT between 2° and 25°C (36° and 77°F).

OPTIVAR® 0.2 mL container: Store at controlled room temperature 20°-25°C (68° -77°F).

Rx Only

U.S. Patent 5,164,194

OPTIVAR® 6 mL container Manufactured by: Patheon UK Ltd., Swindon, United Kingdom

OPTIVAR® 0.2 mL container Manufactured by: Catalent Pharma Solutions, Woodstock, Illinois, USA

Distributed by:

Meda Pharmaceuticals

Meda Pharmaceuticals Inc.

Somerset, New Jersey 08873-4120

OPTIVAR® 6 ml container Made in United Kingdom

OPTIVAR® 0.2 mL container Made in United States

Issued 07/2008                       ANO143-05                       56199040

Package Label - Principal Display Panel – 4-Count Unit Dose Pouch

NDC 0037-7025-01

OPTIVAR®

azelastine hydrochloride

ophthalmic solution, 0.05%

Professional Sample

4 single-use containers

(0.2 mL – Sterile)

Rx only

Meda Pharmaceuticals

Unit-Dose Pouch

Package Label - Principal Display Panel – Carton for 4-Count Unit Dose Pouch

NDC 0037-7025-01

OPTIVAR®

azelastine hydrochloride

ophthalmic solution, 0.05%

Professional Sample

4 single-use containers

(0.2 mL – Sterile)

Rx only

Meda Pharmaceuticals

Unit-Dose Carton

Package Label - Principal Display Panel – 3 mL-fill Bottle

NDC 0037-7025-33

OPTIVAR®

azelastine hydrochloride
ophthalmic solution, 0.05%

Rx Only     3 mL – Sterile

PROFESSIONAL SAMPLE

Usual dosage: 1 drop per affected eye(s) twice daily.
See package insert for full prescribing information.
STORE UPRIGHT between 2° and 25°C (36° and 77°F).
Mfd by: Patheon UK Ltd. Swindon, United Kingdom

Dist by: MedPointe Pharmaceuticals

MedPointe Healthcare Inc.

Somerset, New Jersey 08873

OTD 91010

Rev. 12/04

Made in United Kingdom

Exp. Date

Lot No.

3 mL Bottle

Package Label - Principal Display Panel – Carton for 3 mL-fill Bottle

NDC 0037-7025-33

OPTIVAR®

azelastine hydrochloride
ophthalmic solution, 0.05%

Professional
Sample

3 mL - Sterile

Rx Only

MedPointe Pharmaceuticals

3 mL Carton

Package Label - Principal Display Panel – 6 mL-fill

NDC 0037-7025-60

OPTIVAR®

azelastine hydrochloride
ophthalmic solution, 0.05%

Rx Only     6 mL – Sterile

Usual dosage: 1 drop per affected eye(s) twice daily.
See package insert for full prescribing information.
STORE UPRIGHT between 2° and 25°C (36° and 77°F).
Mfd by: Patheon UK Ltd. Swindon, United Kingdom

Dist by: MedPointe Pharmaceuticals

MedPointe Healthcare Inc.

Somerset, New Jersey 08873

OTD 90940

Rev. 12/04

Made in United Kingdom

Exp. Date
Lot No.

6 mL Bottle

Package Label - Principal Display Panel – Carton for 6 mL-fill Bottle

NDC 0037-7025-60

OPTIVAR®

azelastine hydrochloride

ophthalmic solution, 0.05%

6 mL - Sterile

Rx Only

MedPointe Pharmaceuticals

6 mL Carton


OPTIVAR 
azelastine hydrochloride   solution/ drops
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)0037-7025
Route of AdministrationINTRAOCULARDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
AZELASTINE HYDROCHLORIDE (AZELASTINE) AZELASTINE HYDROCHLORIDE.5 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
BENZALKONIUM CHLORIDE125 ug  in 1 mL
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
10037-7025-011 POUCH In 1 BOXcontains a POUCH
14 VIAL In 1 POUCHThis package is contained within the BOX (0037-7025-01) and contains a VIAL, SINGLE-DOSE
1.2 mL In 1 VIAL, SINGLE-DOSEThis package is contained within a POUCH and a BOX (0037-7025-01)
20037-7025-331 BOTTLE In 1 BOXcontains a BOTTLE, PLASTIC
23 mL In 1 BOTTLE, PLASTICThis package is contained within the BOX (0037-7025-33)
30037-7025-601 BOTTLE In 1 BOXcontains a BOTTLE, PLASTIC
36 mL In 1 BOTTLE, PLASTICThis package is contained within the BOX (0037-7025-60)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA02112705/22/2000

Labeler - Meda Pharmaceuticals Inc. (051229602)
Revised: 06/2009Meda Pharmaceuticals Inc.