Ophthalmologicals; decongestant and antiallergics; other antiallergics. ATC code:
Olopatadine is a potent selective antiallergic/antihistaminic agent that exerts its effects through multiple distinct mechanisms of actions. It antagonizes histamine (the primary mediator of allergic response in humans) and prevents histamine induced inflammatory cytokine production by human conjunctival epithelial cells. Data from in vitro studies suggest that it may act on human conjunctival mast cells to inhibit the release of pro-inflammatory mediators. In patients with patent nasolacrimal ducts, topical ocular administration of Olopatadine Eye Drops, Solution was suggested to reduce the nasal signs and symptoms that frequently accompany seasonal allergic conjunctivitis. It does not produce a clinically significant change in pupil diameter.
Olopatadine was absorbed into the eye and reached maximal levels (Cmax
) within 30 minutes to 2 hours (Tmax
) in ocular tissues following bilateral single topical ocular instillation of 1 drop of increasing dose strengths of Olopatadine (0.15%, 0.2% and 0.7%) in Male New Zealand White (NZW) Rabbits. Plasma levels of Olopatadine were low (Cmax
<20 ng/mL) following bilateral topical ocular administration of 0.15%/0.2%/0.7% Olopatadine ophthalmic solution to rabbits.
In the humans, plasma levels following topical ocular administration (2 drops of 0.1% in both eyes, four times-daily, 4 days; 2 drops of 0.15% in both eyes, twice daily, 14 days; 2 drops of 0.2% in both eyes, twice daily, 7 days; 1 drop of 0.77% in each eye for 7 days) and oral administration (20 mg, twice daily, 13.5 days) are shown in Table 1. Compared with the oral administration exposure on Day 12, the mean exposure estimates show Olopatadine Cmax
(1.64 ng/mL) and AUC0-12
(9.68 ngh/mL) after multiple 0.77% topical ocular doses was 184-fold and 102-fold lower than the Cmax
(302 ng/mL) and AUC0-12
(987 ngh/mL) after multiple 20 mg oral doses of Olopatadine. These data indicate that topical ocular doses of 0.77% Olopatadine hydrochloride ophthalmic solution has a wide margin of safety since it resulted in a systemic exposure that is much lower than that after oral doses of 20 mg Olopatadine hydrochloride. (See Table 1.)
Click on icon to see table/diagram/image
Studies in rabbits show ocular tissues associated with the site of dosing i.e., conjunctiva and cornea, had the highest concentrations of Olopatadine after bilateral single topical ocular instillation of 1 drop of increasing dose strengths of Olopatadine (0.15%, 0.2% and 0.7%) in Male New Zealand White (NZW) Rabbits. Olopatadine concentrations in aqueous humor, choroids, ICB and lens increases with increasing concentrations of Olopatadine. Studies conducted in pigmented Dutch belted rabbits indicated a low degree of binding to melanin pigmented tissues.
Studies have not been conducted to investigate the metabolism of Olopatadine in ocular tissues since toxicology and clinical studies have shown it to be safe and effective. The major metabolites of Olopatadine following oral administration in humans are N-desmethyl Olopatadine (M1) and Olopatadine N-oxide (M3). N-desmethyl Olopatadine (M1) is almost exclusively demethylated by the cytochrome P-450 isozyme 3A4 (CYP3A4). Olopatadine was not an inhibitor of cytochrome P-450 isozymes and therefore drug-drug interactions due to metabolic interactions were not expected.
In the humans after topical ocular administration, N-desmethyl metabolite of Olopatadine (M1) was not quantifiable (≤0.050 ng/mL) in plasma sample in all subjects.
Studies have not been conducted to investigate the excretion of Olopatadine in the urine or feces after topical ocular instillation. In rats after 14
C oral administration, Olopatadine was rapidly eliminated from the body primarily by urinary excretion and biotransformation (metabolism). In humans, urinary excretion of unchanged drug was the major route of elimination.
Studies conducted to investigate the elimination of Olopatadine in rabbits showed concentrations of Olopatadine in various ocular tissues (aqueous humor, choroid, conjunctiva, cornea, and ICB) over the dose strengths (0.1 to 0.7% ophthalmic solution) declined with a half-life of less than 4.65 hours.
In humans, the systemic plasma half-life was less than 3 hours.
In a single dose study, Olopatadine showed a dose proportional increasing in exposure (Cmax
and AUC) in ocular tissues after topical ocular instillation.
Toxicology: Preclinical Safety Data:
Non-clinical data reveal no special hazard for humans treated with Olopatadine Hydrochloride Eye Drops, Solution at concentrations up to and including 0.7% based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.
Effects in non-clinical reproductive and developmental toxicity studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
Oral doses of up to 400 mg/kg/day (~40,000-fold higher than the prescribed dose in a 50 kg adult treated with the highest concentration of Olopatadine commercially available, 0.7%) resulted in some general toxicity, but had no effect on fertility and general reproductive parameters when either males or females were treated prior to and through mating. No effects were observed on embryo-fetal development in rats or rabbits treated with Olopatadine orally, by gavage, at doses of up to 600 mg/kg/day and 400 mg/kg/day, respectively. Peri- and postnatal toxicity studies in rats demonstrated maternal toxicity, and reduced pup survival and weights at the highest dose of 600 mg/kg/day (~60,000-fold higher than the prescribed dose in a 50 kg adult treated with the highest concentration of Olopatadine commercially available, 0.7%), administered to the dam during late gestation and the lactation period. Pup viability and weight gain were also reduced at dose levels of 60 and 200 mg/kg/day. Olopatadine has been detected in the milk of nursing rats following oral administration.