Teva-Olopatadine Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

TEVA-OLOPATADINE (olopatadine hydrochloride) Ophthalmic Solution, 0.1% is indicated for the treatment of allergic conjunctivitis

Geriatrics: No overall difference in safety has been observed between elderly and younger patients.

Pediatrics (3 – 16 years of age): Olopatadine hydrochloride 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.

CONTRAINDICATIONS

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.

WARNINGS AND PRECAUTIONS

General

For topical use only. Not for injection. Patients should be instructed not to instill TEVA-OLOPATADINE 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

Fertility: 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.

Special Populations

Pregnant Women:

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.

Nursing Women:

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 TEVA-OLOPATADINE 0.1% (olopatadine hydrochloride) Ophthalmic Solution is administered to a nursing mother.

Geriatrics: No overall difference in safety has been observed between elderly and younger patients.

Pediatrics (3 – 16 years of age): Safety and effectiveness in pediatric patients between the ages of 3 and 16 have been established.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In clinical studies of olopatadine hydrochloride ophthalmic solution, 0.1% 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

Abnormal Hematologic and Clinic Chemistry Findings

No hematologic or clinical chemistry findings have been observed.

Post-Market Adverse Drug Reactions

Approximately 30.5 million units of olopatadine hydrochloride ophthalmic solution have been sold in 69 countries. The reporting rate of all reaction terms reported between 01 January 1997 and 31 December 2004 was 0.004%, and no single reaction term occurred with a reporting rate greater than 0.0007%.

There were no new major findings bearing on the established overall safety profile of olopatadine hydrochloride ophthalmic solution.

DRUG INTERACTIONS

Overview

No clinical interaction studies have been conducted with olopatadine hydrochloride ophthalmic solution. In vitro studies have shown that olopatadine does not inhibit metabolic reactions which involve cytochrome P-450 isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. Olopatadine is moderately bound to plasma proteins (approximately 55%).These results indicate that olopatadine is unlikely to result in interactions with other concomitantly administered medications. Due to the low systemic exposure following topical ocular dosing, it is unlikely that with olopatadine hydrochloride ophthalmic solution would interfere with immediate hypersensitivity skin testing.

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.

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

The recommended dose is one to two drops in each affected eye twice daily. No dosage adjustment is required in hepatic or renal impairment.

Missed Dose

If a dose is missed, a single drop should be taken as soon as possible before reverting to regular routine. Do not use a double dose to make up for the one missed.

OVERDOSAGE

A topical overdosage may be flushed from the eye(s) with warm tap water. For management of a suspected drug overdose, contact your regional Poison Control Centre.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Olopatadine, a structural analog of doxepin, is a non-steroidal, non-sedating, topically effective anti-allergic molecule that exerts its effects through multiple distinct mechanisms of action. Olopatadine is a mast cell stabilizer and a potent, selective histamine H₁ antagonist (9, 11) that inhibits the in vivo type 1 immediate hypersensitivity reaction (12). Olopatadine inhibits the release of mast cell inflammatory mediators [i.e., histamine, tryptase, prostaglandin D2 and TNFα (4,9,11,12)] as demonstrated in in vitro studies and confirmed in patients (7). Olopatadine is also an inhibitor of pro-inflammatory cytokine secretion from human conjunctival epithelial cells (13).

Pharmacodynamics

Effects on cardiac repolarization (QTc):

In two placebo-controlled, two-way crossover cardiac repolarization studies, no signal of QT interval prolongation was observed relative to placebo following twice daily 5 mg oral doses for 2.5 days in 102 healthy volunteers, or following twice daily 20 mg oral doses for 13.5 days in 32 healthy volunteers. In addition, no evidence of QT interval prolongation was observed, relative to placebo, in 429 perennial allergic rhinitis patients given olopatadine hydrochloride Nasal Spray, 665 micrograms twice daily for up to 1 year.

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). 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.

Special Populations and Conditions:

Pediatrics: Olopatadine hydrochloride 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.

Geriatrics: No overall difference in safety has been observed between elderly and younger patients.

Gender: No specific pharmacokinetic study examining the effect of gender was conducted.

Race: No specific pharmacokinetic study examining the effect of race was conducted.

Hepatic Insufficiency: No specific pharmacokinetic study examining the effect of hepatic impairment was conducted. Since metabolism of olopatadine is a minor route of elimination, no adjustment of the dosing regimen of olopatadine hydrochloride ophthalmic solution, 0.1% is warranted in patients with hepatic impairment.

Renal Insufficiency:

The mean plasma C_max values for olopatadine following single intranasal doses of olopatadine HCl nasal spray 0.6% (665 μg/spray) were not markedly different between healthy subjects (18.1 ng/mL) and patients with mild, moderate and severe renal impairment (range 15.5 to 21.6 ng/mL). Plasma AUC was 2.5-fold higher in patients with severe impairment (creatinine clearance <30 mL/min/1 .73m2). Predicted peak steady-state plasma concentrations of olopatadine in patients with renal impairment following administration of olopatadine hydrochloride ophthalmic solution, 0.1% are at least 10-fold lower than those observed following administration of olopatadine nasal spray 0.6%, and approximately 300-fold lower than those observed following the safe and well-tolerated administration of 20 mg oral doses for 13.5 days. These findings indicate that no adjustment of the dosing regimen of olopatadine hydrochloride ophthalmic solution, 0.1% is warranted in patients with renal impairment.

STORAGE AND STABILITY

Store at 4° - 30°C. Protect from direct sunlight. Discard container at the end of treatment.

SPECIAL HANDLING INSTRUCTIONS

None.

DOSAGE FORMS, COMPOSITION AND PACKAGING

TEVA-OLOPATADINE (olopatadine hydrochloride) Ophthalmic Solution, 0.1% is available in plastic bottle dispensers containing 5 mL.

Each mL of TEVA-OLOPATADINE sterile 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 water for injection.

TEVA-OLOPATADINE solution has a pH of approximately 7 and an osmolality of approximately 300 mOsm/kg.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name: olopatadine hydrochloride

Chemical name: 11-[(Z) -3-(Dimethylamino)propylidene]-6,11-dihydrodibenz[b,e] oxepin-2-acetic acid hydrochloride

Molecular formula: C₂₁H₂₄ClNO₃

Molecular mass: 373.87

Structural formula:

Description: White or whitish powder

Solubility: Sparingly soluble in water.

pH (in aqueous solution): 2.68

CLINICAL TRIALS

In well controlled clinical studies, olopatadine hydrochloride ophthalmic solution produced significantly less ocular discomfort (burning and stinging) compared to Acular® (ketorolac tromethamine) 0.5% Sterile Ophthalmic Solution and Livostin^™ 0.05% (levocabastine hydrochloride ophthalmic suspension). Olopatadine hydrochloride ophthalmic solution also had significantly less effects on visual clarity relative to both Acular® (ketorolac tromethamine) 0.5% Sterile Ophthalmic Solution and Livostin^TM 0.05% (levocabastine hydrochloride ophthalmic suspension).

DETAILED PHARMACOLOGY

Olopatadine is an anti-allergic agent that exerts its effects through multiple distinct mechanisms of action. Olopatadine is a mast cell stabilizer and a potent, selective histamine H1 antagonist (10) that inhibits the in vivo type 1 immediate hypersensitivity reaction. In vitro studies have demonstrated the ability of olopatadine to stabilize human conjunctival mast cells and inhibit immunologically-stimulated release of histamine. In addition, olopatadine inhibits the release of other mast cell inflammatory mediators [i.e., histamine, tryptase, prostaglandin D2 and TNFα (4,9,11,12)] 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 histamine binding and histamine-stimulated vascular permeability in the conjunctiva following topical ocular administration (11). Olopatadine is also an inhibitor of pro-inflammatory cytokine secretion from human conjunctival epithelial cells (13). Decreased chemotaxis and inhibition of eosinophil activation has also been reported (6,8). Olopatadine is devoid of effects on alphaadrenergic, dopamine, muscarinic type 1 and 2, and serotonin receptors.

Human Pharmacodynamics

Olopatadine had no observed effect on heart rate, cardiac conduction (PR and QRS interval duration), cardiac repolarization (QT duration) or wave form morphology relative to placebo in 2 double-masked, placebo controlled, 2-way crossover studies of 102 subjects given 5-mg oral doses of olopatadine every 12 hours for 2.5 days and 32 subjects given 20-mg oral doses twice daily for 13.5 days [C-00-23 and C-02-54]. No clinically relevant or statistically significant changes in mean QTcF (determined to be the most appropriate heart correction formula for both study populations) at steady-state from baseline were observed in either study. A categorical analysis of QTc (< 30 ms, 30 ms-60 ms, or> 60 ms) showed no statistically significant differences between olopatadine and placebo in both studies. An analysis of the maximal change from baseline in QTcF showed the difference was higher for placebo than for olopatadine.

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 greater than 300 fold below those observed with a well-tolerated 20 mg 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.

MICROBIOLOGY

Not applicable.

TOXICOLOGY

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.

Antigenicity: 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.

REFERENCES

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