rst safety trial, patients were treated with an investigational formulation of olopatadine hydrochloride nasal spray containing povidone (not the commercially marketed formulation) or a vehicle nasal spray containing povidone. nasal septal perforations were reported in one patient treated with the investigational formulation of olopatadine hydrochloride nasal spray and 2 patients treated with the vehicle nasal spray. in the second safety trial with olopatadine hydrochloride nasal spray, which does not contain povidone, there were no reports of nasal septal perforation. in the third safety trial, one patient exposed to the 3.7 ph vehicle nasal spray (containing no povidone) reported a nasal septal perforation [ see adverse reactions ( 6.1 ) ]. before starting olopatadine hydrochloride nasal spray, conduct a nasal examination to ensure that patients are free of nasal disease other than allergic rhinitis. perform nasal examinations periodically for signs of adverse effects on the nasal mucosa and consider stopping olopatadine hydrochloride nasal spray if patients develop nasal ulcerations. 5.2 somnolence and impaired mental alertness in clinical trials, the occurrence of somnolence has been reported in some patients taking olopatadine hydrochloride nasal spray [ see adverse reactions ( 6.1 ) ]. patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery after administration of olopatadine hydrochloride nasal spray. concurrent use of olopatadine hydrochloride nasal spray with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur.

ial priming. re-priming (as needed): when olopatadine hydrochloride nasal spray has not been used for more than 7 days, re-prime by releasing 2 sprays. avoid spraying olopatadine hydrochloride nasal spray into the eyes. discard instructions : discard nasal device after 240 sprays (enough for 30 days of dosing) have been used even though the bottle is not completely empty. the correct amount of medication cannot be assured after 240 sprays have been used.

another drug and may not reflect the rates observed in practice. the safety data described below reflect exposure to olopatadine hydrochloride nasal spray in 2770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of 2 weeks to 12 months duration. olopatadine hydrochloride nasal spray is not indicated for use in patients with perennial allergic rhinitis. the safety data from adults and adolescents are based upon 6 placebo-controlled clinical trials (3.7 ph vehicle nasal spray or 7.0 ph vehicle nasal spray) in which 1834 patients with seasonal or perennial allergic rhinitis (652 males and 1182 females) 12 years of age and older were treated with olopatadine hydrochloride nasal spray two sprays per nostril twice daily. there were 1180 patients (olopatadine hydrochloride nasal spray, 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. there were 2840 patients (olopatadine hydrochloride nasal spray, 1247; 3.7 ph vehicle nasal spray, 1251; 7.0 ph vehicle nasal spray, 342) that participated in 3 long-term clinical trials of 1-year duration. the racial distribution of adult and adolescent patients receiving olopatadine hydrochloride nasal spray was 77% white, 9% black, and 14% other. the incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for olopatadine hydrochloride nasal spray and vehicle nasal spray. overall, 4.7% of the 1834 adult and adolescent patients across all 6 studies treated with olopatadine hydrochloride nasal spray, 3.5% of the 1844 patients treated with 3.7 ph vehicle nasal spray discontinued due to adverse reactions, and 2.9% of the 342 patients treated with 7.0 ph vehicle nasal spray discontinued due to adverse reactions. the safety data from pediatric patients 6 to 11 years of age are based upon 3 clinical trials in which 870 children with seasonal allergic rhinitis (376 females and 494 males) were treated with olopatadine hydrochloride nasal spray one or two sprays per nostril twice daily for 2 weeks. the racial distribution of pediatric patients receiving olopatadine hydrochloride nasal spray was 68.6% white, 16.6% black, and 14.8% other. the incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for olopatadine hydrochloride nasal spray and vehicle nasal spray. overall, 1.4% of the 870 pediatric patients across all 3 studies treated with olopatadine hydrochloride nasal spray and 1.3% of the 872 pediatric patients treated with vehicle nasal spray discontinued due to adverse reactions. adults and adolescents 12 years of age and older in short-term (2-week) trials there were 1180 patients 12 years of age and older (olopatadine hydrochloride nasal spray, 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. table 1 presents the most common adverse reactions (0.9% or greater in patients treated with olopatadine hydrochloride nasal spray) that occurred more frequently in patients treated with olopatadine hydrochloride nasal spray compared with vehicle nasal spray in the 3 clinical trials of 2 weeks duration. table 1: adverse reactions occurring at an incidence of 0.9% or greater in controlled clinical trials of 2 weeks duration with olopatadine hydrochloride nasal spray in adolescent and adult patients 12 years of age and older with seasonal allergic rhinitis adverse reaction adult and adolescent patients 12 years and older olopatadine hydrochloride nasal spray n = 587 vehicle nasal spray n = 593 bitter taste 75 (12.8%) 5 (0.8%) headache 26 (4.4%) 24 (4.0%) epistaxis 19 (3.2%) 10 (1.7%) pharyngolaryngeal pain 13 (2.2%) 8 (1.3%) post-nasal drip 9 (1.5%) 5 (0.8%) cough 8 (1.4%) 3 (0.5%) urinary tract infection 7 (1.2%) 3 (0.5%) cpk elevation 5 (0.9%) 2 (0.3%) dry mouth 5 (0.9%) 1 (0.2%) fatigue 5 (0.9%) 4 (0.7%) influenza 5 (0.9%) 1 (0.2%) nasopharyngitis 5 (0.9%) 4 (0.7%) somnolence 5 (0.9%) 2 (0.3%) throat irritation 5 (0.9%) 0 (0.0%) there were no differences in the incidence of adverse reactions based on gender or race. clinical trials did not include sufficient numbers of patients 65 years of age and older to determine whether they respond differently from younger subjects. pediatric patients 6 to 11 years of age there were 1742 pediatric patients 6 to 11 years of age (olopatadine nasal spray, 870; vehicle nasal spray, 872) with seasonal allergic rhinitis that participated in 3 clinical trials of 2 weeks duration. two of the studies used the investigational formulation of olopatadine nasal spray, and one of the studies used olopatadine hydrochloride nasal spray. one study evaluated the safety of olopatadine hydrochloride nasal spray at doses of one and two sprays per nostril twice daily in 1188 patients, in which 298 were exposed to olopatadine hydrochloride nasal spray 1 spray, 296 were exposed to olopatadine hydrochloride nasal spray 2 sprays, 297 were exposed to vehicle 1 spray, and 297 were exposed to vehicle 2 sprays twice daily for 2 weeks. table 2 presents the most common adverse reactions (greater than 1.0% in pediatric patients 6 to 11 years of age treated with olopatadine hydrochloride nasal spray one spray per nostril) that occurred more frequently with olopatadine hydrochloride nasal spray compared with vehicle nasal spray. table 2. adverse reactions occurring at an incidence of greater than 1.0% in a controlled clinical trial of 2 weeks duration with olopatadine hydrochloride nasal spray in pediatric patients 6 to 11 years of age with seasonal allergic rhinitis adverse reaction pediatric patients 6 to 11 years of age olopatadine hydrochloride nasal spray one spray per nostril n = 298 vehicle nasal spray one spray per nostril n = 297 epistaxis headache upper respiratory tract infection bitter taste 17 (5.7%) 13 (4.4%) 8 (2.6%) 3 (1.0%) 11 (3.7%) 11 (3.7%) 0 0 pyrexia 4 (1.3%) 3 (1.0%) rash 4 (1.3%) 0 there were no differences in the incidence of adverse reactions based on gender, race, or ethnicity. long-term (12 month) safety trials in a 12-month, placebo-controlled, safety trial (vehicle nasal spray), 890 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal spray two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). in the olopatadine hydrochloride nasal spray and vehicle nasal spray groups, 72% and 74% of patients, respectively, completed the trial. overall, 7% and 5%, respectively, discontinued study participation due to an adverse reaction. the most frequently reported adverse reaction was epistaxis, which occurred in 25% of patients treated with olopatadine hydrochloride nasal spray and 28% in patients treated with vehicle nasal spray. epistaxis resulted in discontinuation of 0.9% of patients treated with olopatadine hydrochloride nasal spray and 0.2% of patients treated with vehicle nasal spray. nasal ulcerations occurred in 10% of patients treated with olopatadine hydrochloride nasal spray and 9% of patients treated with vehicle nasal spray. nasal ulcerations resulted in discontinuation of 0.4% of patients treated with olopatadine hydrochloride nasal spray and 0.2% patients treated with vehicle nasal spray. there were no patients with nasal septal perforation in either treatment group. somnolence was reported in 1 patient treated with olopatadine hydrochloride nasal spray and 1 patient treated with vehicle nasal spray. weight increase was reported in 6 patients treated with olopatadine hydrochloride nasal spray and 1 patient treated with vehicle nasal spray. depression or worsening of depression occurred in 9 patients treated with olopatadine hydrochloride nasal spray and in 5 patients treated with vehicle nasal spray. three patients, 2 of whom had preexisting histories of depression, who received olopatadine hydrochloride nasal spray were hospitalized for depression compared to none who received vehicle nasal spray. in a second 12-month, placebo-controlled, safety trial (vehicle nasal spray), 459 patients 12 years of age and older with perennial allergic rhinitis were treated with two sprays per nostril of an investigational formulation of olopatadine hydrochloride nasal spray containing povidone (not the commercially marketed formulation) and 465 patients were treated with 2 sprays of a vehicle nasal spray containing povidone. nasal septal perforations were reported in one patient treated with the investigational formulation of olopatadine hydrochloride nasal spray and 2 patients treated with the vehicle nasal spray. epistaxis was reported in 19% of patients treated with the investigational formulation of olopatadine hydrochloride nasal spray and 12% of patients treated with vehicle nasal spray. somnolence was reported in 3 patients treated with the investigational formulation of olopatadine hydrochloride nasal spray compared to 1 patient treated with vehicle nasal spray. fatigue was reported in 5 patients treated with the investigational formulation of olopatadine hydrochloride nasal spray compared to 1 patient treated with vehicle nasal spray. in a third 3-arm, 12-month, placebo-controlled, safety trial (vehicle nasal spray), conducted post approval, 1026 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine hydrochloride nasal spray (343 patients), a 3.7 ph vehicle nasal spray (341 patients), or a 7.0 ph vehicle nasal spray (342 patients). all treatments were administered as two sprays per nostril, twice daily. overall, 5% of olopatadine hydrochloride nasal spray patients, 2% of 3.7 ph vehicle patients and 3% of 7.0 ph vehicle patients discontinued due to adverse reactions. the most frequently reported adverse reaction was epistaxis, which occurred in 24% of patients treated with olopatadine hydrochloride nasal spray, 20% of patients treated with 3.7 ph vehicle nasal spray, and 23% of patients treated with 7.0 ph vehicle nasal spray. epistaxis resulted in the discontinuation of 2 patients treated with olopatadine hydrochloride nasal spray and 1 patient treated with 7.0 ph vehicle nasal spray. nasal septal perforation was reported for one patient treated with the 3.7 ph vehicle nasal spray. nasal ulcerations occurred in 9% of patients treated with olopatadine hydrochloride nasal spray, 8% of patients treated with 3.7 ph vehicle nasal spray, and 9% of patients treated with 7.0 ph vehicle nasal spray. nasal ulceration resulted in the discontinuation of 1 patient treated with olopatadine hydrochloride nasal spray. hyposmia and anosmia were each reported by one patient treated with olopatadine hydrochloride nasal spray. neither somnolence nor weight loss was reported. depression occurred in 3 patients treated with olopatadine hydrochloride nasal spray, 2 patients treated with 3.7 ph vehicle nasal spray, and 3 patients treated with 7.0 ph vehicle nasal spray. there were no long-term clinical trials in children below 12 years of age. 6.2 postmarketing experience during the post approval use of olopatadine hydrochloride nasal spray, the following adverse reactions have been identified. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. the most common adverse reactions reported include dizziness, dysgeusia, epistaxis, headache, nasal discomfort, oropharyngeal pain, and somnolence. additionally, hyposmia and anosmia have been reported with the use of olopatadine hydrochloride nasal spray.

nd miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively. data animal data in an oral embryo-fetal development study, pregnant rabbits were dosed throughout the period of organogenesis at doses up to 400 mg/kg/day. a decrease in the number of live fetuses was observed at 400 mg/kg/day (1460 times the mrhdid, on a mg/m 2 basis). in an oral embryo-fetal development study, pregnant rats were dosed throughout the period of organogenesis at doses up to 600 mg/kg/day. maternal toxicity, producing death and reduced maternal body weight gain was observed at 600 mg/kg/day (approximately 1100 times the mrhdid on a mg/m 2 basis). olopatadine produced cleft palate at 60 mg/kg/day (approximately 110 times the mrhdid on a mg/m 2 basis) and decreased embryo-fetal viability and reduced fetal weight in rats at 600 mg/kg/day (approximately 1100 times the mrhdid on a mg/m 2 basis). in peri-/postnatal toxicity studies, pregnant rats received oral doses of olopatadine up to 600 mg/kg/day during late gestation and throughout the lactation period. olopatadine produced decreased neonatal survival at 60 mg/kg/day (approximately 110 times the mrhdid on a mg/m 2 basis) and reduced body weight gain in pups at 4 mg/kg/day (approximately 7 times the mrhdid on a mg/m 2 basis). these effects appeared attributable to exposure of pups via the milk as demonstrated in a cross-fostered study in which pups of untreated dams cross-fostered to dams treated with 60 mg/kg/day olopatadine orally during the lactation period exhibited decreased body weight gain. 8.2 lactation risk summary there are no data on the presence of olopatadine in human milk, the effects on the breastfed infant, or the effects on milk production. although orally administered olopatadine is present in rat milk, there is no information about nasally administered olopatadine. it is not known whether topical nasal administration could result in sufficient systemic absorption to produce detectable quantities in human breast milk. the developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olopatadine hydrochloride nasal spray and any potential adverse effects on the breast fed infant from olopatadine hydrochloride nasal spray or from the underlying maternal condition. 8.4 pediatric use the safety and effectiveness of olopatadine hydrochloride nasal spray for the relief of symptoms of seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. the safety and effectiveness of olopatadine hydrochloride nasal spray in pediatric patients 6 to 11 years of age are supported by 3 vehicle-controlled 2-week studies in 870 patients [ see adverse reactions ( 6.1 ) ]. doses studied included one and two sprays per nostril twice daily. one of these studies evaluated the safety of olopatadine hydrochloride nasal spray at doses of one and two sprays per nostril twice daily in 1,188 patients, of which 298 patients were exposed to olopatadine hydrochloride nasal spray 1 spray and 297 patients were exposed to vehicle 1 spray. in this study, the incidence of epistaxis with olopatadine hydrochloride nasal spray use was 5.7% [see adverse reactions ( 6.1 ), clinical studies ( 14 )]. the safety and effectiveness of olopatadine hydrochloride nasal spray in pediatric patients aged 12 years and older are supported by 3 randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials of 2 weeks duration in adult and adolescent patients [see clinical studies ( 14 )] . in these studies, the incidence of epistaxis with olopatadine hydrochloride nasal spray use in 587 patients was 3.2% [see adverse reactions ( 6.1 )] . the safety and effectiveness of olopatadine hydrochloride nasal spray have not been established in pediatric patients under 6 years of age. the safety of olopatadine hydrochloride nasal spray at a dose of one spray per nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 pediatric patients 2 to 5 years of age with allergic rhinitis. in this trial, 66 patients were exposed to olopatadine hydrochloride nasal spray. the most common (greater than 1.0%) adverse reactions reported were diarrhea (9.1%), epistaxis (6.1%), rhinorrhea (4.5%), bitter taste (3.0%) and wheezing (3.0%). diarrhea was reported more frequently (9.1%) in patients 2 to 5 years of age than 6 to 11 year old age group (< 1%). 8.5 geriatric use clinical studies of olopatadine hydrochloride nasal spray did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients. other reported clinical experience has not identified differences in responses between the elderly and younger patients. in general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease or other drug therapy.

ecognized pregnancies is 2% to 4%, and 15% to 20%, respectively. data animal data in an oral embryo-fetal development study, pregnant rabbits were dosed throughout the period of organogenesis at doses up to 400 mg/kg/day. a decrease in the number of live fetuses was observed at 400 mg/kg/day (1460 times the mrhdid, on a mg/m 2 basis). in an oral embryo-fetal development study, pregnant rats were dosed throughout the period of organogenesis at doses up to 600 mg/kg/day. maternal toxicity, producing death and reduced maternal body weight gain was observed at 600 mg/kg/day (approximately 1100 times the mrhdid on a mg/m 2 basis). olopatadine produced cleft palate at 60 mg/kg/day (approximately 110 times the mrhdid on a mg/m 2 basis) and decreased embryo-fetal viability and reduced fetal weight in rats at 600 mg/kg/day (approximately 1100 times the mrhdid on a mg/m 2 basis). in peri-/postnatal toxicity studies, pregnant rats received oral doses of olopatadine up to 600 mg/kg/day during late gestation and throughout the lactation period. olopatadine produced decreased neonatal survival at 60 mg/kg/day (approximately 110 times the mrhdid on a mg/m 2 basis) and reduced body weight gain in pups at 4 mg/kg/day (approximately 7 times the mrhdid on a mg/m 2 basis). these effects appeared attributable to exposure of pups via the milk as demonstrated in a cross-fostered study in which pups of untreated dams cross-fostered to dams treated with 60 mg/kg/day olopatadine orally during the lactation period exhibited decreased body weight gain.

e nasal spray in pediatric patients aged 12 years and older are supported by 3 randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials of 2 weeks duration in adult and adolescent patients [see clinical studies ( 14 )] . in these studies, the incidence of epistaxis with olopatadine hydrochloride nasal spray use in 587 patients was 3.2% [see adverse reactions ( 6.1 )] . the safety and effectiveness of olopatadine hydrochloride nasal spray have not been established in pediatric patients under 6 years of age. the safety of olopatadine hydrochloride nasal spray at a dose of one spray per nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 pediatric patients 2 to 5 years of age with allergic rhinitis. in this trial, 66 patients were exposed to olopatadine hydrochloride nasal spray. the most common (greater than 1.0%) adverse reactions reported were diarrhea (9.1%), epistaxis (6.1%), rhinorrhea (4.5%), bitter taste (3.0%) and wheezing (3.0%). diarrhea was reported more frequently (9.1%) in patients 2 to 5 years of age than 6 to 11 year old age group (< 1%).

han 60 msec, and no subjects had qtcf values greater than 500 msec. in a 12-month study in 429 perennial allergic rhinitis patients treated with olopatadine hydrochloride nasal spray two sprays per nostril twice daily, no evidence of any effect of olopatadine hydrochloride on qt prolongation was observed. 12.3 pharmacokinetics the pharmacokinetic properties of olopatadine were studied after administration by the nasal, oral, intravenous, and topical ocular routes. olopatadine exhibited linear pharmacokinetics across the routes studied over a large dose range. absorption healthy subjects: olopatadine was absorbed with individual peak plasma concentrations observed between 30 minutes and 1 hour after twice daily intranasal administration of olopatadine hydrochloride nasal spray. the mean ( ± sd) steady-state peak plasma concentration (c max ) of olopatadine was 16.0 ± 8.99 ng/ml. systemic exposure as indexed by area under the curve (auc 0-12 ) averaged 66.0 ± 26.8 ng·h/ml. the average absolute bioavailability of intranasal olopatadine is 57%. the mean accumulation ratio following multiple intranasal administration of olopatadine hydrochloride nasal spray was about 1.3. seasonal allergic rhinitis patients: systemic exposure of olopatadine in seasonal allergic rhinitis (sar) patients after twice daily intranasal administration of olopatadine hydrochloride nasal spray was comparable to that observed in healthy subjects. olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and 2 hours. the mean steady-state c max was 23.3 ± 6.2 ng/ml and auc 0-12 averaged 78.0 ± 13.9 ng·h/ml. distribution the protein binding of olopatadine was moderate at approximately 55% in human serum, and independent of drug concentration over the range of 0.1 to 1000 ng/ml. olopatadine was bound predominately to human serum albumin. elimination the plasma elimination half-life of olopatadine is 8 to 12 hours. olopatadine is mainly eliminated through urinary excretion. approximately 70% of a [ 14 c] olopatadine hydrochloride oral dose was recovered in urine with 17% in the feces. of the drug-related material recovered within the first 24 hours in the urine, 86% was unchanged olopatadine with the balance comprised of olopatadine n-oxide and n-desmethyl olopatadine. metabolism olopatadine is not extensively metabolized. based on plasma metabolite profiles following oral administration of [ 14 c] olopatadine, at least six minor metabolites circulate in human plasma. olopatadine accounts for 77% of peak plasma total radioactivity and all metabolites amounted to < 6% combined. two of these have been identified as the olopatadine n-oxide and n-desmethyl olopatadine. in in vitro studies with cdna-expressed human cytochrome p450 isoenzymes (cyp) and flavin-containing monooxygenases (fmo), n-desmethyl olopatadine (ml) formation was catalyzed mainly by cyp3a4, while olopatadine n-oxide (m3) was primarily catalyzed by fmo1 and fmo3. olopatadine at concentrations up to 33,900 ng/ml did not inhibit the in vitro metabolism of specific substrates for cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a4. the potential for olopatadine and its metabolites to act as inducers of cyp enzymes has not been evaluated. specific populations patients with hepatic impairment 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 nasal spray is warranted in patients with hepatic impairment. patients with renal impairment the mean c max values for olopatadine following single nasal doses 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). the mean plasma auc 0-12 was 2-fold higher in patients with severe impairment (creatinine clearance < 30 ml/min/1.73 m 2 ). in these patients, peak steady-state plasma concentrations of olopatadine are approximately 10-fold lower than those observed after higher 20 mg oral doses, twice daily, which were well-tolerated. these findings indicate that no adjustment of the dosing regimen of olopatadine hydrochloride nasal spray is warranted in patients with renal impairment. male and female patients the mean systemic exposure (c max and auc 0-12 ) in female sar patients following multiple administration of olopatadine was 40% and 27% higher, respectively than those values observed in male sar patients. racial or ethnic groups the effects of race on olopatadine pharmacokinetics have not been adequately investigated. pediatric patients 6 to 11 years of age the systemic pharmacokinetics of olopatadine, olopatadine n-oxide and n-desmethyl olopatadine in patients 6 through 11 years of age were characterized using data from 42 pediatric patients administered olopatadine hydrochloride nasal spray, one spray per nostril twice daily for a minimum of 14 days. the mean c max (15.4 ± 7.3 ng/ml) of olopatadine was approximately 2-fold less than was comparable to that observed in adults (78.0 ± 13.9 ng·h/ml). the c max and auc 0-12 of olopatadine n-oxide were comparable to that observed in adults. the c max and auc 0-12 of n-desmethyl olopatadine are approximately 18% and 37% higher than that observed in adults, respectively. pediatric patients 2 to 5 years of age the systemic pharmacokinetics of olopatadine, olopatadine n-oxide, and n-desmethyl olopatadine were characterized using population pharmacokinetic methods applied to sparse data (approximately 5 samples per patient) obtained from 66 pediatric patients (2 to less than 6 years of age) administered one-half the recommended adult dose (one spray per nostril) of olopatadine hydrochloride nasal spray twice daily for a minimum of 14 days. the mean c max and auc 0-12 of olopatadine were 13.4 ± 4.6 ng/ml and 75.0 ± 26.4 ng•hr/ml respectively. the mean c max and auc 0-12 of olopatadine n-oxide and n-desmethyl olopatadine were similar to that of patients 6 to 11 years of age. drug interaction studies drug interactions with inhibitors of liver enzymes are not anticipated because olopatadine is eliminated predominantly by renal excretion. olopatadine did not inhibit the in vitro metabolism of specific substrates for cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a4. based on these data, drug interactions involving p450 inhibition are not expected. due to the modest protein binding of olopatadine (55%), drug interactions through displacement from plasma proteins are also not expected.

ients after twice daily intranasal administration of olopatadine hydrochloride nasal spray was comparable to that observed in healthy subjects. olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and 2 hours. the mean steady-state c max was 23.3 ± 6.2 ng/ml and auc 0-12 averaged 78.0 ± 13.9 ng·h/ml. distribution the protein binding of olopatadine was moderate at approximately 55% in human serum, and independent of drug concentration over the range of 0.1 to 1000 ng/ml. olopatadine was bound predominately to human serum albumin. elimination the plasma elimination half-life of olopatadine is 8 to 12 hours. olopatadine is mainly eliminated through urinary excretion. approximately 70% of a [ 14 c] olopatadine hydrochloride oral dose was recovered in urine with 17% in the feces. of the drug-related material recovered within the first 24 hours in the urine, 86% was unchanged olopatadine with the balance comprised of olopatadine n-oxide and n-desmethyl olopatadine. metabolism olopatadine is not extensively metabolized. based on plasma metabolite profiles following oral administration of [ 14 c] olopatadine, at least six minor metabolites circulate in human plasma. olopatadine accounts for 77% of peak plasma total radioactivity and all metabolites amounted to < 6% combined. two of these have been identified as the olopatadine n-oxide and n-desmethyl olopatadine. in in vitro studies with cdna-expressed human cytochrome p450 isoenzymes (cyp) and flavin-containing monooxygenases (fmo), n-desmethyl olopatadine (ml) formation was catalyzed mainly by cyp3a4, while olopatadine n-oxide (m3) was primarily catalyzed by fmo1 and fmo3. olopatadine at concentrations up to 33,900 ng/ml did not inhibit the in vitro metabolism of specific substrates for cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a4. the potential for olopatadine and its metabolites to act as inducers of cyp enzymes has not been evaluated. specific populations patients with hepatic impairment 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 nasal spray is warranted in patients with hepatic impairment. patients with renal impairment the mean c max values for olopatadine following single nasal doses 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). the mean plasma auc 0-12 was 2-fold higher in patients with severe impairment (creatinine clearance < 30 ml/min/1.73 m 2 ). in these patients, peak steady-state plasma concentrations of olopatadine are approximately 10-fold lower than those observed after higher 20 mg oral doses, twice daily, which were well-tolerated. these findings indicate that no adjustment of the dosing regimen of olopatadine hydrochloride nasal spray is warranted in patients with renal impairment. male and female patients the mean systemic exposure (c max and auc 0-12 ) in female sar patients following multiple administration of olopatadine was 40% and 27% higher, respectively than those values observed in male sar patients. racial or ethnic groups the effects of race on olopatadine pharmacokinetics have not been adequately investigated. pediatric patients 6 to 11 years of age the systemic pharmacokinetics of olopatadine, olopatadine n-oxide and n-desmethyl olopatadine in patients 6 through 11 years of age were characterized using data from 42 pediatric patients administered olopatadine hydrochloride nasal spray, one spray per nostril twice daily for a minimum of 14 days. the mean c max (15.4 ± 7.3 ng/ml) of olopatadine was approximately 2-fold less than was comparable to that observed in adults (78.0 ± 13.9 ng·h/ml). the c max and auc 0-12 of olopatadine n-oxide were comparable to that observed in adults. the c max and auc 0-12 of n-desmethyl olopatadine are approximately 18% and 37% higher than that observed in adults, respectively. pediatric patients 2 to 5 years of age the systemic pharmacokinetics of olopatadine, olopatadine n-oxide, and n-desmethyl olopatadine were characterized using population pharmacokinetic methods applied to sparse data (approximately 5 samples per patient) obtained from 66 pediatric patients (2 to less than 6 years of age) administered one-half the recommended adult dose (one spray per nostril) of olopatadine hydrochloride nasal spray twice daily for a minimum of 14 days. the mean c max and auc 0-12 of olopatadine were 13.4 ± 4.6 ng/ml and 75.0 ± 26.4 ng•hr/ml respectively. the mean c max and auc 0-12 of olopatadine n-oxide and n-desmethyl olopatadine were similar to that of patients 6 to 11 years of age. drug interaction studies drug interactions with inhibitors of liver enzymes are not anticipated because olopatadine is eliminated predominantly by renal excretion. olopatadine did not inhibit the in vitro metabolism of specific substrates for cyp1a2, cyp2c9, cyp2c19, cyp2d6, cyp2e1 and cyp3a4. based on these data, drug interactions involving p450 inhibition are not expected. due to the modest protein binding of olopatadine (55%), drug interactions through displacement from plasma proteins are also not expected.

flective or instantaneous scores. reflective scoring required patients to record symptom severity over the previous 12 hours; the instantaneous scoring required patients to record symptom severity at the time of recording. the primary efficacy endpoint was the difference from placebo in the percent change from baseline in the average of morning and evening reflective total nasal symptom score (rtnss) averaged for the 2-week treatment period. in all 3 trials, patients treated with olopatadine hydrochloride nasal spray, two sprays per nostril, twice-daily, exhibited statistically significantly greater decreases in rtnss compared to vehicle nasal spray. results for the rtnss from 2 representative trials are shown in table 3. table 3: mean reflective total nasal symptom score (rtnss) in adult and adolescent patients with seasonal allergic rhinitis study no. treatment n baseline change from baseline difference from placebo estimate 95% ci p-value study 1 olopatadine hydrochloride nasal spray 0.6% 183 8.71 -3.63 -0.96 (-1.42, -0.51) <0.0001 olopatadine hydrochloride nasal spray 0.4% 188 8.90 -3.38 -0.71 (-1.17, -0.26) 0.0023 vehicle nasal spray 191 8.75 -2.67 study 2 olopatadine hydrochloride nasal spray 0.6% 220 9.17 -2.90 -0.98 (-1.37, -0.59) <0.0001 olopatadine hydrochloride nasal spray 0.4% 228 9.26 -2.63 -0.72 (-1.11, -0.33) 0.0003 vehicle nasal spray 223 9.07 -1.92 abbreviation: ci, confidence interval. itchy eyes and watery eyes were evaluated as secondary endpoints but eye redness was not evaluated. in 2 of the studies, patients treated with olopatadine hydrochloride nasal spray had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray. in the 2-week seasonal allergy trials, onset of action was also evaluated by instantaneous tnss assessments twice-daily after the first dose of study medication. in these trials, onset of action was seen after 1 day of dosing. onset of action was evaluated in 3 environmental exposure unit studies with single doses of olopatadine hydrochloride nasal spray. in these studies, patients with seasonal allergic rhinitis were exposed to high levels of pollen in the environmental exposure unit and then treated with either olopatadine hydrochloride nasal spray or vehicle nasal spray, two sprays in each nostril, after which they self-reported their allergy symptoms hourly as instantaneous scores for the subsequent 12 hours. olopatadine hydrochloride nasal spray 0.6% was found to have an onset of action of 30 minutes after dosing in the environmental exposure unit. pediatric patients 6 to 11 years of age there were 3 clinical trials of 2 weeks duration with olopatadine nasal spray in patients 6 to 11 years of age with seasonal allergic rhinitis. efficacy of olopatadine hydrochloride nasal spray was evaluated in 2 of the 3 trials. one of the 2 trials that showed efficacy was a randomized, double blind, parallel group, multicenter, placebo (vehicle nasal spray)-controlled clinical trial of 2 weeks duration, including 1188 children ages 6 to < 12 years with seasonal allergic rhinitis. assessment of efficacy was based on patient/caregiver recording of 4 individual nasal symptoms (nasal congestion, rhinorrhea, itchy nose, and sneezing) on a 0 to 3 categorical severity scale (0 = absent, 1 = mild, 2 = moderate, 3 = severe) as reflective or instantaneous scores. reflective scoring captured symptom severity over the previous 12 hours; the instantaneous scoring captured symptom severity at the time of recording. the primary efficacy endpoint was the difference from placebo in the percent change from baseline in the average of patient/caregiver-reported morning and evening reflective total nasal symptom score (rtnss) averaged for the 2-week treatment period. patients treated with olopatadine hydrochloride nasal spray, one or two sprays per nostril twice daily, had statistically significantly greater decreases in rtnss compared to vehicle nasal spray. results for rtnss are shown in table 4. table 4: mean reflective total nasal symptom score in pediatric patients 6 to 11 years of age with seasonal allergic rhinitis treatment n baseline change from baseline difference from placebo estimate 95% ci p-value olopatadine hydrochloride nasal spray 0.6%, one spray per nostril twice daily 294 8.99 -2.24 -0.55 (-0.90, -0.19) 0.0015 vehicle nasal spray, one spray per nostril twice daily 294 9.09 -1.70 abbreviation: ci, confidence interval. itchy eyes and watery eyes were evaluated as secondary endpoints in the same study but eye redness was not evaluated. patients treated with olopatadine hydrochloride nasal spray had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray.

her central nervous system depressants advise patients that concurrent use of olopatadine hydrochloride nasal spray with alcohol or other central nervous system depressants should be avoided because additional reductions in alertness and additional impairment of central nervous system performance may occur [ see warnings and precautions ( 5.2 ) ]. keep spray out of eyes inform patients to avoid spraying olopatadine hydrochloride nasal spray in their eyes [ see dosage and administration ( 2.3 ) ]. made in israel manufactured by padagis yeruham, israel distributed by padagis allegan, mi 49010 ● www.padagis.com rev 11-21 4s000 rc j5

and your healthcare provider should decide if you will use olopatadine hydrochloride nasal spray if you plan to breastfeed. tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. olopatadine hydrochloride nasal spray and other medicines may affect each other and cause side effects. know the medicines you take. keep a list of your medicines and show it to your healthcare provider or pharmacist when you get a new medicine. how should i use olopatadine hydrochloride nasal spray? • see the “instructions for use” at the end of this patient information leaflet for information about the right way to use olopatadine hydrochloride nasal spray. • olopatadine hydrochloride nasal spray is for use in your nose only. do not spray it in your eyes or mouth. • use olopatadine hydrochloride nasal spray exactly as your healthcare provider tells you to use it. • do not use more than your healthcare provider tells you. • if you use too much olopatadine hydrochloride nasal spray, call your healthcare provider or pharmacist right away • throw away olopatadine hydrochloride nasal spray after 240 sprays (about 30 days) after the first priming. even though the bottle may not be completely empty, you may not get the correct dose of medicine if you continue to use it. what should i avoid while using olopatadine hydrochloride nasal spray? • olopatadine hydrochloride nasal spray can cause sleepiness or drowsiness. do not drive, operate machinery, or do anything that needs you to be alert until you know how olopatadine hydrochloride nasal spray affects you. • do not drink alcohol or take any medicines that may cause you to feel sleepy while using olopatadine hydrochloride nasal spray. it may make your sleepiness worse. what are the possible side effects of olopatadine hydrochloride nasal spray? olopatadine hydrochloride nasal spray may cause serious side effects, including: • nosebleeds. • sores in the nose. • hole in the cartilage between the nose (nasal septum perforation). a whistling sound when you breathe may be a symptom of nasal septum perforation. • sleepiness or drowsiness. the most common side effects of olopatadine hydrochloride nasal spray in people 12 years of age and older include: • bad or bitter taste • headache • throat pain • nose congestion • cough • urinary tract infection the most common side effects of olopatadine hydrochloride nasal spray in people 6 to 11 years of age include: • headache • upper respiratory tract infection • bad or bitter taste • fever • rash tell your healthcare provider if you have any side effect that bothers you or that does not go away. these are not all of the possible side effects of olopatadine hydrochloride nasal spray. for more information, ask your healthcare provider or pharmacist. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store olopatadine hydrochloride nasal spray? • store olopatadine hydrochloride nasal spray at room temperature between 39°f to 77°f (4°c to 25°c). • do not use your olopatadine hydrochloride nasal spray after the expiration date on the label or box. keep olopatadine hydrochloride nasal spray and all medicines out of the reach of children. general information about olopatadine hydrochloride nasal spray. medicines are sometimes prescribed for conditions that are not mentioned in the patient information leaflet. do not use olopatadine hydrochloride nasal spray for a condition for which it was not prescribed. do not give olopatadine hydrochloride nasal spray to other people, even if they have the same symptoms you have. it may harm them. you can ask your healthcare provider or pharmacist for information about olopatadine hydrochloride nasal spray that is written for health professionals. what are the ingredients in olopatadine hydrochloride nasal spray? active ingredient: olopatadine hydrochloride 665 micrograms per spray. inactive ingredients: 0.01% benzalkonium chloride, dibasic sodium phosphate, edetate disodium, hydrochloric acid and/or sodium hydroxide, purified water and sodium chloride. made in israel manufactured by padagis yeruham, israel distributed by padagis allegan, mi 49010 for more information, go to www.padagis.com or call 1-866-634-9120. 4s000 rc j5 this patient information has been approved by the u.s. food and drug administration. revised: 11/2021