SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 3 ADVERSE REACTIONS 4 DRUG INTERACTIONS 5 DOSAGE AND ADMINISTRATION 5 OVERDOSAGE 5 ACTION AND CLINICAL PHARMACOLOGY 5 STORAGE AND STABILITY 6 SPECIAL HANDLING INSTRUCTIONS 7 DOSAGE FORMS, COMPOSITION AND PACKAGING 7
PHARMACEUTICAL INFORMATION 8 CLINICAL TRIALS 8 DETAILED PHARMACOLOGY 9 MICROBIOLOGY 9 TOXICOLOGY 9 REFERENCES 10
PATANOL(r) (Olopatadine Hydrochloride) Ophthalmic Solution, 0.1%
| Route of Administration | Dosage Form / Strength | Clinically Relevant Nonmedicinal Ingredients |
| topical ophthalmic | solution 0.1% (w/v) | Preservative: benzalkonium chloride Inactive Ingredients: purified water, sodium chloride, dibasic sodium phosphate, hydrochloric acid and/or sodium hydroxide (to adjust pH) |
PATANOL (olopatadine hydrochloride) Ophthalmic Solution, 0.1% is indicated for
treatment of allergic conjunctivitis
Geriatrics:
No data is available.
Pediatrics (3 - 16 years of age):
PATANOL Ophthalmic Solution administered three times a day for six weeks was shown to be safe and well-tolerated in subjects who were ages 3 years and older.
Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see Dosage Forms, Composition and Packaging section of the product monograph.
General
For topical use only. Not for injection. Patients should be instructed not to instill PATANOL 0.1% (Olopatadine Hydrochloride) Ophthalmic Solution while wearing contact lenses, but to wait for 10 minutes after instillation before inserting contact lenses. 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.
Carcinogenesis and Mutagenesis
Please refer to animal data in TOXICOLOGY section.
Sexual Function/Reproduction
Olopatadine administered to male and female rats at oral doses of 62,500 times the maximum recommended ocular human use 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. No teratogenic effects were observed in rats and rabbits at oral doses >90,000 and >60,000 times the maximum recommended ocular human use level, respectively.
Special Populations
Olopatadine was found not to be teratogenic in rats and rabbits at oral doses >90,000 and >60,000 times the maximum recommended ocular human use level, respectively. 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.
Olopatadine has been identified in the milk of nursing rats following oral administration. Rat pups of mothers administered olopatadine orally at greater than 625 times (but not at 312 times) the maximum recommended ocular human use level demonstrated reduced body weight gain during the nursing period. It is not known whether topical ocular administration could result in sufficient systemic absorption to produce detectable quantities in human breast milk. Nevertheless, caution should be exercised when PATANOL 0.1% (olopatadine hydrochloride) Ophthalmic Solution is administered to a nursing mother.
Safety and effectiveness in pediatric patients between the ages of 3 and 16 have been established.
No data is available.
Adverse Drug Reaction Overview
In clinical studies of PATANOL 0.1% (olopatadine hydrochloride) Ophthalmic Solution, ocular and nonocular adverse reactions related to therapy were reported at an incidence below 1%.
Clinical Trial Adverse Drug Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
Less Common Clinical Trial Adverse Drug Reactions (<1%)
Ocular:
mild transient burning or stinging, pruritis, hyperemia, foreign body sensation, superficial keratitis, lid edema, dry eye, lid dryness, lid spasm, photophobia
Nonocular:
asthenia, headache, taste perversion
Drug-Drug Interactions
Interactions with other drugs have not been established.
Drug-Food Interactions
Interactions with food have not been established.
Drug-Herb Interactions
Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
Recommended Dose and Dosage Adjustment
The recommended dose is one to two drops in each affected eye twice daily.
A topical overdosage may be flushed from the eye(s) with warm tap water.
Mechanism of Action
Olopatadine is a mast cell stabilizer and a potent, selective histamine H1 antagonist that inhibits the in vivo type 1 immediate hypersensitivity reaction. In vitro studies have demonstrated the ability of olopatadine to stabilize rodent basophils and human conjunctival mast cells and inhibit antigen-stimulated release of histamine. In addition, olopatadine inhibits the release of other mast cell inflammatory mediators (i.e., tryptase and prostaglandin D2) as demonstrated in in vitro studies. Olopatadine is a selective histamine H1 receptor antagonist in vitro and in vivo as demonstrated by its ability to inhibit binding and histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Olopatadine is also an inhibitor of pro- inflammatory cytokine secretion from human conjunctival epithelial cells. Olopatadine is devoid of effects on alpha-adrenergic, dopamine, muscarinic type 1 and 2, and serotonin receptors.
Pharmacokinetics
Following topical ocular administration in man, olopatadine was shown to have low systemic exposure. Two studies in normal volunteers (totalling 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. These plasma concentrations were approximately 2 to 3 orders of magnitude below those observed with well tolerated oral multiple dose regimens. In oral studies, olopatadine was found to be well absorbed. The half-life in plasma was 7-14 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.
PATANOL Ophthalmic Solution administered three times a day for six weeks was shown to be safe and well tolerated in subjects who were 3 years and older.
No specific pharmacokinetic study examining the effect of patients above 65 years of age was conducted.
No specific pharmacokinetic study examining the effect of gender was conducted.
No specific pharmacokinetic study examining the effect of race was conducted.
No specific pharmacokinetic study examining the effect of hepatic
impairment was conducted.
No specific pharmacokinetic study examining the effect of renal impairment was conducted.
Store at 4deg - 30degC.
None.
PATANOL(r) (olopatadine hydrochloride) Ophthalmic Solution, 0.1% is available in plastic DROP-TAINER(r) dispensers containing 5 mL, 10 mL or 15mL. Each mL of PATANOL Ophthalmic Solution contains: Active: 1.11 mg olopatadine hydrochloride equivalent to 1 mg olopatadine. Preservative: benzalkonium chloride 0.01%. Inactives: sodium chloride, dibasic sodium phosphate, hydrochloric acid/sodium hydroxide (adjust pH), and purified water.
PART II: SCIENTIFIC INFORMATION
Proper name: olopatadine hydrochloride Chemical name: (Z)-11-[3-(Dimethylamino)propylidene]-6-11-dihydrodibenz[b,e]- oxepine-2-acetic acid, hydrochloride Molecular formula and molecular mass: C21H23NO3 * HCl; 373.88 Structural formula:
CH3
N CH3 H
CO2H
.
HCl
O
Description: White, crystalline powder Solubility: Sparingly soluble in methanol and water. Insoluble in chloroform. pH (1% aqueous solution): 2.5
Results from conjunctival antigen challenge studies demonstrated that PATANOL (olopatadine hydrochoride) Ophthalmic Solution, 0.1% when challenged with antigen both initially and up to 8 hours after dosing was significantly more effective than placebo in preventing ocular itching and redness associated with allergic conjunctivitis. In a placebo-controlled clinical study designed to evaluate safety, PATANOL Ophthalmic Solution administered three times a day for six weeks was shown to be safe and well-tolerated in subjects who were ages 3 years and older. In well controlled clinical studies, PATANOL Ophthalmic Solution produced significantly less ocular discomfort (burning and stinging) compared to Acular(r) (ketorolac tromethamine) 0.5% Sterile Ophthalmic Solution and Livostin(tm) 0.05% (levocabastine hydrochloride ophthalmic suspension).
Olopatadine is a mast cell stabilizer and a potent, selective histamine H1 antagonist that inhibits the in vivo type 1 immediate hypersensitivity reaction. In vitro studies have demonstrated the ability of olopatadine to stabilize rodent basophils and human conjunctival mast cells and inhibit antigen-stimulated release of histamine. In addition, olopatadine inhibits the release of other mast cell inflammatory mediators (i.e., tryptase and prostaglandin D2) as demonstrated in in vitro studies. Olopatadine is a selective histamine H1 receptor antagonist in vitro and in vivo as demonstrated by its ability to inhibit binding and histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration. Olopatadine is also an inhibitor of pro- inflammatory cytokine secretion from human conjunctival epithelial cells. Olopatadine is devoid of effects on alpha-adrenergic, dopamine, muscarinic type 1 and 2, and serotonin receptors. Human Pharmacokinetics Following topical ocular administration in man, olopatadine was shown to have low systemic exposure. Two studies in normal volunteers (totalling 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. These plasma concentrations were approximately 2 to 3 orders of magnitude below those observed with a well-tolerated oral multiple-dose regimen. In oral studies, olopatadine was found to be well absorbed. The half-life in plasma was 7-14 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.
Not applicable.
The acute toxicity of olopatadine hydrochloride has been investigated in mice, rats and dogs. Mice and rats demonstrated that olopatadine hydrochloride was not an acute toxicity hazard with oral LD50 values greater than 1150 mg/kg and 3870 mg/kg for mice and rats, respectively. Subchronic and chronic oral toxicity studies in rats and dogs demonstrated that the liver and kidney were target organs for olopatadine hydrochloride toxicity. In rats, ophthalmology and hematology parameters were unaffected following chronic administration of olopatadine hydrochloride. In chronic dog studies, ophthalmology, hematology, blood chemistry and organ weight parameters were unaffected by olopatadine hydrochloride administration. A one-month topical ocular study was conducted with 0.1% (QID) or 0.2% Olopatadine hydrochloride (QID and HID) Ophthalmic Solution in New Zealand White (NZW) rabbits. No signs of pharmacotoxicity were observed. Slit-lamp and indirect ocular evaluations and pachymetry revealed no treatment-related findings. Clinical pathology data and histopathology were unremarkable. Chronic topical ocular studies were conducted with olopatadine hydrochloride in rabbits and monkeys. Administration of olopatadine hydrochloride at concentrations of 0.1, 0.5 and 1.0% QID to NZW rabbits elicited no signs of pharmacotoxicity. No treatment-related findings were observed during slit-lamp and indirect ocular evaluations and pachymetry measurements. Clinical pathology data and histopathology were unremarkable. Similar findings were observed following six months of topical ocular administration of olopatadine hydrochloride at concentrations of 0.1, 0.2 and 0.5% QID to cynomolgus monkeys. Olopatadine was not carcinogenic in mice and rats of either sex at doses up to 78,000 and 31,000 times the maximum recommended ocular human use level, respectively. 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 hydrochloride was demonstrated to have a low potential for antigenicity when tested in mice and guinea pigs or in an in vitro passive hemagglutination test.
Allansmith MR, Ross R. Ocular allergy. Clinical Allergy 18:1-13, 1988.
Allansmith MR, Ross R. Ocular allergy and mast cell stabilizers. Survey of Ophthalmology 30:226-244,1986.
Friedlander MH. Conjunctival provocative tests: a model of human ocular allergy. Trans Am Ophthalmologic Soc. 577-97, 1989.
Weimer LK, Gamache DA, Yanni JM. Histamine-stimulated cytokine secretion from human conjunctival epithelial cells: Inhibition by histamine H1 antagonists. Int Arch Allergy Immunol 115:288-293, 1998.
Yanni JM, Weimer LK, Sharif NA, Xu SX, Gamache DA, Spellman JM. Inhibition of histamine-induced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol 117:643-647, 1999.
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