NDA 20-688/SLR-016
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`Patanol
`(olopatadine hydrochloride ophthalmic solution) 0.1%
`
`DESCRIPTION
`PATANOL® (olopatadine hydrochloride ophthalmic solution) 0.1 % is a sterile ophthalmic solution
`containing olopatadine, a relatively selective H1-receptor antagonist and inhibitor of histamine release
`from the mast cell for topical administration to the eyes. Olopatadine hydrochloride is a white,
`crystalline, water-soluble powder with a molecular weight of 373.88. The chemical structure is
`presented below:
`
`Chemical Name: 11-[(Z)-3-(Dimethylamino)propylidene]-6-11-dihydrodibenz[b,e] oxepin-2-acetic
`acid hydrochloride
`
`[Structure]
`
`Each mL of PATANOL contains: Active: 1.11 mg olopatadine hydrochloride equivalent to 1 mg
`olopatadine.
`Preservative: benzalkonium chloride 0.01 %. Inactives: dibasic sodium phosphate; sodium chloride;
`hydrochloric acid/sodium hydroxide (adjust pH); and purified water. It has a pH of approximately 7
`and an osmolality of approximately 300 mOsm/kg.
`
` DM-00
`
`CLINICAL PHARMACOLOGY
`Olopatadine is an inhibitor of the release of histamine from the mast cell and a relatively selective
`histamine H1-antagonist that inhibits the in vivo and in vitro type 1 immediate hypersensitivity reaction
`including inhibition of histamine induced effects on human conjunctival epithelial cells. Olopatadine is
`devoid of effects on alpha-adrenergic, dopamine and muscarinic type 1 and 2 receptors. Following
`topical ocular administration in man, olopatadine was shown to have low systemic exposure. Two
`studies in normal volunteers (totaling 24 subjects) dosed bilaterally with olopatadine 0.15%
`ophthalmic solution once every 12 hours for 2 weeks demonstrated plasma concentrations to be
`generally below the quantitation limit of the assay (<0.5 ng/mL). Samples in which olopatadine was
`quantifiable were typically found within 2 hours of dosing and ranged from 0.5 to 1.3 ng/mL. The
`half-life in plasma was approximately 3 hours, and elimination was predominantly through renal
`excretion. Approximately 60-70% of the dose was recovered in the urine as parent drug. Two
`metabolites, the mono-desmethyl and the N-oxide, were detected at low concentrations in the urine.
`
`Results from an environmental study demonstrated that PATANOL was effective in the treatment of
`the signs and symptoms of allergic conjunctivitis when dosed twice daily for up to 6 weeks. Results
`from conjunctival antigen challenge studies demonstrated that PATANOL, when subjects were
`challenged with antigen both initially and up to 8 hours after dosing, was significantly more effective
`than its vehicle in preventing ocular itching associated with allergic conjunctivitis.
`
`INDICATIONS AND USAGE
`PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1 % is indicated for the treatment of the
`signs and symptoms of allergic conjunctivitis.
`
`CONTRAINDICATIONS
`PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1 % is contraindicated in persons with a
`known hypersensitivity to olopatadine hydrochloride or any components of PATANOL.
`
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`APOTEX EX1037
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`NDA 20-688/SLR-016
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`WARNINGS
`PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1% is for topical 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 the eyelids or surrounding areas with the dropper tip of the bottle. Keep bottle tightly
`closed when not in use.
`Patients should be advised not to wear a contact lens if their eye is red. PATANOL® (olopatadine
`hydrochloride ophthalmic solution) 0.1 % should not be used to treat contact lens related irritation. The
`preservative in PATANOL, 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 PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1% before they
`insert their contact lenses.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility: Olopatadine administered orally was not
`carcinogenic in mice and rats in doses up to 500 mg/kg/day and 200 mg/kg/day, respectively. Based on
`a 40 µL drop size, these doses were 78,125 and 31,250 times higher than the maximum recommended
`ocular human dose (MROHD). No mutagenic potential was observed when olopatadine was tested in
`an in vitro bacterial reverse mutation (Ames) test, an in vitro mammalian chromosome aberration assay
`or an in vivo mouse micronucleus test. Olopatadine administered to male and female rats at oral doses
`of 62,500 times MROHD level resulted in a slight decrease in the fertility index and reduced
`implantation rate; no effects on reproductive function were observed at doses of 7,800 times the
`maximum recommended ocular human use level.
`
`Pregnancy: Pregnancy Category C. Olopatadine was found not to be teratogenic in rats and rabbits.
`However, rats treated at 600 mg/kg/day, or 93,750 times the MROHD and rabbits treated at 400
`mg/kg/day, or 62,500 times the MROHD, during organogenesis showed a decrease in live fetuses.
`There are, however, no adequate and well controlled studies in pregnant women. Because animal
`studies are not always predictive of human responses, this drug should be used in pregnant women
`only if the potential benefit to the mother justifies the potential risk to the embryo or fetus.
`
`Nursing Mothers: Olopatadine has been identified in the milk of nursing rats following oral
`administration. It is not known whether topical ocular administration could result in sufficient systemic
`absorption to produce detectable quantities in the human breast milk. Nevertheless, caution should be
`exercised when PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1% is administered to a
`nursing mother.
`
`Pediatric Use: Safety and effectiveness in pediatric patients below the age of 3 years have not been
`established.
`
`Geriatric Use: No overall differences in safety or effectiveness have been observed between elderly
`and younger patients.
`
`ADVERSE REACTIONS
`Headaches have been reported at an incidence of 7%. The following adverse experiences have been
`reported in less than 5% of patients: Asthenia, blurred vision, burning or stinging, cold syndrome, dry
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`eye, foreign body sensation, hyperemia, hypersensitivity, keratitis, lid edema, nausea, pharyngitis,
`pruritis, rhinitis, sinusitis, and taste perversion. Some of these events were similar to the underlying
`disease being studied.
`
`DOSAGE AND ADMINISTRATION
`The recommended dose is one drop in each affected eye two times per day at an interval of 6 to 8
`hours.
`
`HOW SUPPLIED
`PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1% is supplied as follows: 5 mL in
`plastic DROP-TAINER© dispenser.
`
`5 mL: NDC 0065-0271-05
`
`Storage: Store at 39°F-77°F (4°C-25°C)
`
`Rx Only
`U.S. Patents Nos. 4,871,865; 4,923,892; 5,116,863; 5,641,805.
`©2000, 2002 Alcon Laboratories, Inc.
`
`Alcon
`ALCON LABORATORIES, INC.
`Fort Worth, Texas 76134 USA
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`PatGER-0802 Revised: August 2002
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