Product Monograph - Apo-Olopatadine (Apotex, 0.1 %)
SUMMARY PRODUCT INFORMATION
| Route of Administration | Dosage Form/ Strength | Clinically Relevant Non-Medicinal Ingredients |
| Topical Ophthalmic | Solution / 0.1% (w/v) | Preservative: benzalkonium chloride |
INDICATIONS AND CLINICAL USE
APO-OLOPATADINE (Olopatadine Hydrochloride Ophthalmic Solution) is indicated for the treatment of allergic conjunctivitis.
Geriatrics:
No overall difference in safety has been observed between elderly and other adult patients.
Pediatrics (3 to 16 years of age):
APO-OLOPATADINE 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 ocular use only. Not for injection or oral use.
As with any eye drop, to prevent contamination of 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 contact lenses if their eye(s) are red.
The preservative in APO-OLOPATADINE, benzalkonium chloride, may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided.
Patients must be instructed to remove contact lenses prior to application of APO-OLOPATADINE, and wait at least 15 minutes before they insert their contact lenses.
If using other eye drops, patients should wait at least 5 minutes between putting in APO-OLOPATADINE and the other drops. Eye ointments should be applied last.
Driving and Using Machinery
Olopatadine is a non-sedating anti-histamine. Temporary blurred vision or other visual disturbances, after the use of APO-OLOPATADINE, may affect the ability to drive or use machines. If blurred vision occurs after instillation, patients must wait until vision clears before driving or using machinery.
Carcinogenesis and Mutagenesis
Please refer to animal data in TOXICOLOGY section.
Sexual Function/Reproduction
Studies have not been performed to evaluate the effect of topical ocular administration of olopatadine on human 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:
There are no adequate and well controlled studies in pregnant women. Studies in animals with Olopatadine have shown reproductive toxicity following systemic administration considered sufficiently in excess of the maximum human exposure. 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. 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 olopatadine hydrochloride ophthalmic solution is administered to a nursing mother.
Geriatrics: No overall difference in safety has been observed between elderly and other adult patients.
Pediatrics (3 to 16 years of age): The safety and effectiveness of APO-OLOPATADINE have been established in pediatric patients between 3 and 16 years of age.
ADVERSE REACTIONS
Adverse Drug Reaction Overview
In clinical studies of olopatadine hydrochloride ophthalmic solution, ocular and non-ocular 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
Ocular: ocular discomfort (including mild transient burning or stinging and foreign body sensation), eye pruritis, ocular hyperemia, superficial keratitis, eyelid edema, dry eye, eyelid dryness, eyelid spasm, photophobia.
Non-ocular: asthenia, headache, dysgeusia.
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.
Adverse drug reactions identified from post-marketing experience that have not been reported previously in the above-mentioned clinical trials with APO-OLOPATADINE include: dizziness, eye pain, eye discharge, eyelid margin crusting, vision blurred, punctate keratitis, keratitis, erythema of eyelid, nasal dryness, dry mouth, dermatitis contact, fatigue, hypersensitivity, lacrimation increased and nausea.
DRUG INTERACTIONS
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 olopatadine hydrochloride ophthalmic solution would interfere with immediate hypersensitivity skin testing.
Interactions with other drugs, food, herbal products or 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
For management of suspected drug overdose, consult your regional poison control centre.
A topical overdosage may be flushed from the eye(s) with warm tap water.
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 mcg 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 to 14 hours, and elimination was predominantly through renal excretion. Approximately 60 to 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 differences in safety and effectiveness have been observed between elderly and other adult 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 Cmax values for olopatadine following single intranasal doses of olopatadine hydrochloride nasal spray 0.6% (665 mcg/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/1.73 m2). 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°C to 30°C. Discard the container at the end of treatment. Keep out of the reach and sight of children.
DOSAGE FORMS, COMPOSITION AND PACKAGING
Composition
APO-OLOPATADINE is a sterile, clear, colourless solution.
Each mL of APO-OLOPATADINE Ophthalmic Solution contains: 1.11 mg olopatadine hydrochloride equivalent to 1 mg olopatadine; benzalkonium chloride 0.02% as preservative; dibasic sodium phosphate, hydrochloric acid/sodium hydroxide (adjust pH), sodium chloride, and water for injection.
Packaging
APO-OLOPATADINE is supplied in a 11 mL white opaque, low-density polyethylene (LDPE) ophthalmic bottle with white translucent LDPE dropper and a white opaque HDPE cap with sealing tape. Each bottle contains 5 mL (partial fill) of APO-OLOPATADINE.
APO-OLOPATADINE Ophthalmic 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: (1) Dibenz[b,e]oxepin-2-acetic acid, 11-[3-(dimethylamino)- propylidene]-6,11-dihydro-, hydrochloride, (Z)- (2) 11-[(Z)-3-(Dimethylamino)propylidene]-6,11-dihydrodibenz- [b,e]oxepin-2-acetic acid, hydrochloride.
Molecular Formula: C21H23NO3 · HCl
Molecular Weight: 373.88 g/mol
Structural Formula:
Physicochemical Properties:
Description:
White to off white, crystalline powder.
Solubility: Sparingly soluble in water and buffer solution
(pH=4.6), slightly soluble in ethanol, very slightly soluble in isopropanol and acetone, soluble in methanol and buffer solution (pH=10).
pH: For a solution in deionized water (5 mg/mL)
2.5 to 4.0.
•HCl H
N
CH3
CH3
| C | O | 2 |
H
O
CLINICAL TRIALS
Study Demographics and Trial Design
| Table 1: Summary of Trial Design and Patient Demographics for Clinical Trials | ||||
| Trial Design | Dosage, Route of Administration and Duration | Study Subjects (n=number) | Mean Age (Range) | Gender |
| Study 1: Randomized, double masked, placebo controlled, parallel group | Placebo, 0.01%, 0.05%, 0.1% and 0.15%; one ophthalmic drop 27 min., 6 hr and 8 hr prior to allergen challenge; 5 weeks | 98 | 37 years (18-64 yrs) | 49 M 49 F |
Study 2: Triple masked, placebo controlled, randomized, contralateral eye comparison study | Placebo, 0.05% and 0.1%; topical ocular administration; 4 weeks | 60 | 46 years (18-72 yrs) | 29 M 31 F |
| Study 3: Triple masked, placebo controlled, randomized contralateral eye comparison study | Placebo, 0.05% and 0.1%; topical ocular administration; 4 weeks | 120 | 39 years (18-80 yrs) | 40 M 80 F |
Study Results
| Table 2: Clinical Trial Study Results | |
| Primary Endpoints | Associated Value and Statistical Significance for Placebo or Active Control |
| Study 1: Onset of action and duration of action for itching and redness | Comparison between the four (4) olopatadine concentrations revealed a non-linear dose relationship. All four (4) concentrations were statistically significant from placebo, however results showed the 0.1% olopatadine concentration to be most effective in reducing ocular itching and redness. At 3, 10 and 20 minutes, olopatadine 0.1% showed a mean point score reduction (range 0-4) in ocular itching compared to placebo of -1.72, -1.68 and -1.28 (P≤0.05), and a -2.72, -3.48 and -2.78 point score reduction (range 0-12) in ocular redness* compared to placebo (P≤0.05) when instilled 27 minutes prior to the conjunctival allergen challenge. Olopatadine 0.1% demonstrated a 6 hour duration of action when instilled 6 hours before the conjunctival allergen challenge. Results show a mean point score reduction (range 0-4) of -1.46, -1.70 and -1.07 in ocular itching compared to placebo (P≤0.05) at 3, 10 and 20 minutes following the allergen challenge. Similarly ocular redness* scores showed a mean -1.52, -1.76 and -1.33 point score reduction (range 0-12) compared to placebo (P≤0.05) at 3, 10 and 20 minutes following the allergen challenge. Olopatadine 0.1% when instilled 8 hours before the conjunctival allergen challenge show a mean point score reduction (range 0-4) of -1.48, -1.62 and -0.92 in ocular itching compared to placebo (P≤0.05) at 3, 10 and 20 minutes following the onset-of-action challenge. Similarly ocular redness* scores showed a mean -1.58, -1.78 and -1.42 point score reduction (range 0-12) compared to placebo (P≤0.05) at 3, 10 and 20 minutes following the onset-of-action challenge. |
| Table 2: Clinical Trial Study Result (Cont'd)s | |
| Primary Endpoints | Associated Value and Statistical Significance for Placebo or Active Control |
| Study 2: Onset of action and duration of action for itching and redness | Olopatadine 0.1% was statistically superior to placebo in preventing ocular itching and redness with 3 minutes of the onset of action challenge. This difference from placebo persisted at the 8 hour duration of action challenge. At 3, 10 and 20 minutes post challenge, olopatadine 0.1% showed a mean point score reduction (range 0-4) in ocular itching compared to placebo of -0.88, -1.19 and -1.07 (P≤0.05), and a -1.60, -1.69 and -1.38 point score reduction (range 0-
|
| Study 3: Onset of action and duration of action for itching and redness | Olopatadine 0.1% was statistically superior to placebo in preventing ocular itching and redness within 3 minutes of the onset of action challenge. This difference from placebo persisted at the 8 hour duration of action challenge. At 3, 10 and 20 minutes post challenge, olopatadine 0.1% showed a mean point score reduction (range 0-4) in ocular itching compared to placebo of -1.25, -1.77 and -1.24 (P≤0.05), and a -2.18, -2.62 and -1.90 point score reduction (range 0-
|
*Ocular redness is calculated as the sum of the ciliary redness (range 0-4), conjunctival redness (range 0-4) and episcleral redness (range 0-4) scores.
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® and Livostin™
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 alpha-adrenergic, 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. 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 to 14 hours, and elimination was predominantly through renal excretion. Approximately 60 to 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.
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 LD5O 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% (4 times a day) or 0.2% Olopatadine hydrochloride (4 and 5 times a day) 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.
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