ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. The most clinically significant adverse reactions described in other sections of labeling include:Epistaxis, Nasal Ulceration, and Nasal Septal Perforation [see Warnings and Precautions (5.1)] Somnolence and Impaired Mental Alertness [see Warnings and Precautions (5.2)] Epistaxis, Nasal Ulceration, and Nasal Septal Perforation [see Warnings and Precautions (5.1)] Somnolence and Impaired Mental Alertness [see Warnings and Precautions (5.2)] The most common (> 1%) adverse reactions, included bitter taste, headache, epistaxis, pharyngolaryngeal pain, post-nasal drip, cough, and urinary tract infection in patients 12 years of age and older and epistaxis, headache, upper respiratory tract infection, bitter taste, pyrexia, and rash in patients to 11 years of age (6.1).To report SUSPECTED ADVERSE REACTIONS, contact Novartis Pharmaceuticals Corporation at 1-888-669-6682 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure to PATANASE in 2770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of weeks to 12 months duration. PATANASE is not indicated for use in patients with perennial allergic rhinitis.The safety data from adults and adolescents are based upon 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 PATANASE two sprays per nostril twice daily. There were 1180 patients (PATANASE, 587; vehicle nasal spray, 593) that participated in efficacy and safety trials of weeks duration. There were 2840 patients (PATANASE, 1247; 3.7 pH vehicle nasal spray, 1251; 7.0 pH vehicle nasal spray, 342) that participated in long-term clinical trials of 1-year duration. The racial distribution of adult and adolescent patients receiving PATANASE was 77% white, 9% black, and 14% other. The incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for PATANASE and vehicle nasal spray. Overall, 4.7% of the 1834 adult and adolescent patients across all studies treated with PATANASE, 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 to 11 years of age are based upon clinical trials in which 870 children with SAR (376 females and 494 males) were treated with PATANASE one or two sprays per nostril twice daily for weeks. The racial distribution of pediatric patients receiving PATANASE 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 PATANASE and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all studies treated with PATANASE 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) TrialsThere were 1180 patients 12 years of age and older (PATANASE, 587; vehicle nasal spray, 593) that participated in efficacy and safety trials of weeks duration. Table presents the most common adverse reactions (0.9% or greater in patients treated with PATANASE) that occurred more frequently in patients treated with PATANASE compared with vehicle nasal spray in the clinical trials of weeks duration.Table 1: Adverse Reactions Occurring at an Incidence of 0.9% or Greater in Controlled Clinical Trials of Weeks Duration With PATANASE in Adolescent and Adult Patients 12 Years of Age and Older With Seasonal Allergic RhinitisAdult and Adolescent Patients 12 Years and OlderAdverse ReactionPATANASEN 587Vehicle Nasal SprayN 593Abbreviation: CPK, creatine phosphokinase.Bitter taste75 (12.8%)5 (0.8%)Headache26 (4.4%)24 (4.0%)Epistaxis19 (3.2%)10 (1.7%)Pharyngolaryngeal Pain13 (2.2%)8 (1.3%)Post-nasal drip9 (1.5%)5 (0.8%)Cough8 (1.4%)3 (0.5%)Urinary tract infection7 (1.2%)3 (0.5%)CPK elevation5 (0.9%)2 (0.3%)Dry mouth5 (0.9%)1 (0.2%)Fatigue5 (0.9%)4 (0.7%)Influenza5 (0.9%)1 (0.2%)Nasopharyngitis5 (0.9%)4 (0.7%)Somnolence5 (0.9%)2 (0.3%)Throat irritation5 (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 to 11 Years of AgeThere were 1742 pediatric patients to 11 years of age (olopatadine nasal spray, 870; vehicle nasal spray, 872) with SAR that participated in clinical trials of weeks duration. Two of the studies used the investigational formulation of olopatadine nasal spray, and one of the studies used PATANASE. One study evaluated the safety of PATANASE at doses of one and two sprays per nostril twice daily in 1188 patients, in which 298 were exposed to PATANASE spray, 296 were exposed to PATANASE sprays, 297 were exposed to vehicle spray, and 297 were exposed to vehicle sprays twice daily for weeks. Table presents the most common adverse reactions (greater than 1.0% in pediatric patients to 11 years of age treated with PATANASE one spray per nostril) that occurred more frequently with PATANASE compared with vehicle nasal spray.Table 2. Adverse Reactions Occurring at an Incidence of Greater Than 1.0% in Controlled Clinical Trial of Weeks Duration With PATANASE in Pediatric Patients to 11 Years of Age With Seasonal Allergic RhinitisPediatric Patients to 11 Years of AgeAdverse ReactionPATANASE One Spray per NostrilN 298Vehicle Nasal Spray One Spray per NostrilN 297EpistaxisHeadacheUpper respiratory tract infectionBitter taste17 (5.7%)13 (4.4%)8 (2.6%)3 (1.0%)11 (3.7%)11 (3.7%)00Pyrexia4 (1.3%)3 (1.0%)Rash4 (1.3%)0There were no differences in the incidence of adverse reactions based on gender, race, or ethnicity.Long-Term (12 month) Safety TrialsIn 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 PATANASE two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). In the PATANASE 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 PATANASE and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of patients treated with PATANASE and 0.2% of patients treated with vehicle nasal spray. Nasal ulcerations occurred in 10% of patients treated with PATANASE and 9% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with PATANASE 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 patient treated with PATANASE and patient treated with vehicle nasal spray. Weight increase was reported in patients treated with PATANASE and patient treated with vehicle nasal spray. Depression or worsening of depression occurred in patients treated with PATANASE and in patients treated with vehicle nasal spray. Three patients, of whom had preexisting histories of depression, who received PATANASE were hospitalized for depression compared to none who received vehicle nasal spray.In 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 PATANASE containing povidone (not the commercially marketed formulation) and 465 patients were treated with sprays of vehicle nasal spray containing povidone. Nasal septal perforations were reported in one patient treated with the investigational formulation of PATANASE and patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated with the investigational formulation of PATANASE and 12% of patients treated with vehicle nasal spray. Somnolence was reported in patients treated with the investigational formulation of PATANASE compared to patient treated with vehicle nasal spray. Fatigue was reported in patients treated with the investigational formulation of PATANASE compared to patient treated with vehicle nasal spray.In 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 PATANASE (343 patients), 3.7 pH vehicle nasal spray (341 patients), or 7.0 pH vehicle nasal spray (342 patients). All treatments were administered as two sprays per nostril, twice daily. Overall, 5% of PATANASE 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 PATANASE, 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 patients treated with PATANASE and 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 PATANASE, 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 patient treated with PATANASE. Hyposmia and anosmia were each reported by one patient treated with PATANASE. Neither somnolence nor weight loss was reported. Depression occurred in patients treated with PATANASE, patients treated with 3.7 pH vehicle nasal spray, and 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 PATANASE, the following adverse reactions have been identified. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 PATANASE.

POSTMARKETING EXPERIENCE SECTION.

6.2 Postmarketing Experience. During the post approval use of PATANASE, the following adverse reactions have been identified. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 PATANASE.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisOlopatadine demonstrated no tumorigenic potential in mice at oral doses up to 500 mg/kg/day (approximately 460 times the MRHDID on mg/m2 basis) for 78 weeks or in rats at oral doses up to 200 mg/kg/day (approximately 370 times the MRHDID on mg/m2 basis) for 104 weeks.MutagenesisNo 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.Impairment of FertilityOlopatadine administered at an oral dose of 400 mg/kg/day, (approximately 730 times the MRHDID for adults on an mg/m2 basis) produced toxicity in male and female rats, and resulted in decrease in the fertility index and reduced implantation rate. No effects on reproductive function were observed at 50 mg/kg/day (approximately 90 times the MRHDID on mg/m2 basis).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Olopatadine is histamine H1 receptor antagonist. The antihistaminic activity of olopatadine has been documented in isolated tissues, animal models, and humans.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn placebo-controlled cardiovascular safety study, 32 healthy volunteers received 20 mg oral solution of olopatadine twice daily for 14 days (8-fold greater daily dose than the recommended daily nasal dose). The mean QTcF (QT corrected by Fridericias correction method for heart rate) change from baseline was -2.7 msec and -3.8 msec for olopatadine, and placebo, respectively. In this study, subjects treated with olopatadine had QTcF change from baseline of 30-60 msec, subject had QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. Eight subjects treated with placebo had QTcF change from baseline of 30-60 msec, no subjects had QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. In 12-month study in 429 perennial allergic rhinitis patients treated with PATANASE 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 large dose range.AbsorptionHealthy Subjects: Olopatadine was absorbed with individual peak plasma concentrations observed between 30 minutes and hour after twice daily intranasal administration of PATANASE. The mean (+- SD) steady-state peak plasma concentration (Cmax) of olopatadine was 16.0 +- 8.99 ng/mL. Systemic exposure as indexed by area under the curve (AUC0-12) 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 PATANASE was about 1.3.Seasonal Allergic Rhinitis Patients: Systemic exposure of olopatadine in SAR patients after twice daily intranasal administration of PATANASE was comparable to that observed in healthy subjects. Olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and hours. The mean steady-state Cmax was 23.3 +- 6.2 ng/mL and AUC0-12 averaged 78.0 +- 13.9 ng.h/mL.DistributionThe 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.EliminationThe plasma elimination half-life of olopatadine is to 12 hours. Olopatadine is mainly eliminated through urinary excretion. Approximately 70% of [14C] 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.MetabolismOlopatadine is not extensively metabolized. Based on plasma metabolite profiles following oral administration of [14C] 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 PopulationsPatients with Hepatic ImpairmentNo specific pharmacokinetic study examining the effect of hepatic impairment was conducted. Since metabolism of olopatadine is minor route of elimination, no adjustment of the dosing regimen of PATANASE is warranted in patients with hepatic impairment.Patients with Renal ImpairmentThe mean Cmax 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 AUC0-12 was 2-fold higher in patients with severe impairment (creatinine clearance 30 mL/min/1.73 m2). 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 PATANASE is warranted in patients with renal impairment.Male and Female PatientsThe mean systemic exposure (Cmax and AUC0-12) 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 GroupsThe effects of race on olopatadine pharmacokinetics have not been adequately investigated.Pediatric Patients to 11 Years of AgeThe systemic pharmacokinetics of olopatadine, olopatadine N-oxide and N-desmethyl olopatadine in patients through 11 years of age were characterized using data from 42 pediatric patients administered PATANASE, one spray per nostril twice daily for minimum of 14 days. The mean Cmax (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 Cmax and AUC0-12 of olopatadine N-oxide were comparable to that observed in adults. The Cmax and AUC0-12 of N-desmethyl olopatadine are approximately 18% and 37% higher than that observed in adults, respectively.Pediatric Patients to Years of AgeThe systemic pharmacokinetics of olopatadine, olopatadine N-oxide, and N-desmethyl olopatadine were characterized using population pharmacokinetic methods applied to sparse data (approximately samples per patient) obtained from 66 pediatric patients (2 to less than years of age) administered one-half the recommended adult dose (one spray per nostril) of PATANASE twice daily for minimum of 14 days. The mean Cmax and AUC0-12 of olopatadine were 13.4 +- 4.6 ng/mL and 75.0+- 26.4 ng.h/mL respectively. The mean Cmax and AUC0-12 of olopatadine N-oxide and N-desmethyl olopatadine were similar to that of patients to 11 years of age.Drug Interaction StudiesDrug 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Adult and Adolescent Patients 12 Years of Age and OlderThe efficacy and safety of PATANASE were evaluated in randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials (vehicle nasal spray) of weeks duration in adult and adolescent patients, 12 years of age and older with symptoms of seasonal allergic rhinitis. The clinical trials were conducted in the United States and included 1598 patients (556 males, and 1042 females) 12 years of age and older. In these trials, 587 patients were treated with PATANASE 0.6%, 418 patients were treated with PATANASE 0.4%, and 593 patients were treated with vehicle nasal spray. Assessment of efficacy was based on patient recording of individual nasal symptoms (nasal congestion, rhinorrhea, itchy nose, and sneezing) on 0 to categorical severity scale (0 absent, = mild, = moderate, = severe) as reflective 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 trials, patients treated with PATANASE, two sprays per nostril, twice-daily, exhibited statistically significantly greater decreases in rTNSS compared to vehicle nasal spray. Results for the rTNSS from representative trials are shown in Table 3.Table 3: Mean Reflective Total Nasal Symptom Score (rTNSS) in Adult and Adolescent Patients With Seasonal Allergic RhinitisStudy No.TreatmentNBaselineChangeFrom BaselineDifference From PlaceboAbbreviation: CI, confidence interval. Estimate95% CIp-valueStudy 1PATANASE Nasal Spray 0.6%1838.71-3.63-0.96(-1.42, -0.51)< 0.0001 PATANASE Nasal Spray 0.4%1888.90-3.38-0.71(-1.17, -0.26)0.0023 Vehicle Nasal Spray1918.75-2.67 Study 2PATANASE Nasal Spray 0.6%2209.17-2.90-0.98(-1.37, -0.59)< 0.0001 PATANASE Nasal Spray 0.4%2289.26-2.63-0.72(-1.11, -0.33)0.0003 Vehicle Nasal Spray2239.07-1.92 Itchy eyes and watery eyes were evaluated as secondary endpoints but eye redness was not evaluated. In of the studies, patients treated with PATANASE 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 day of dosing. Onset of action was evaluated in environmental exposure unit studies with single doses of PATANASE. In these studies, patients with SAR were exposed to high levels of pollen in the environmental exposure unit and then treated with either PATANASE 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. PATANASE 0.6% was found to have an onset of action of 30 minutes after dosing in the environmental exposure unit.Pediatric Patients to 11 Years of AgeThere were clinical trials of weeks duration with olopatadine nasal spray in patients to 11 years of age with seasonal allergic rhinitis. Efficacy of PATANASE was evaluated in of the trials. One of the trials that showed efficacy was randomized, double blind, parallel group, multicenter, placebo (vehicle nasal spray)-controlled clinical trial of weeks duration, including 1188 children ages to 12 years with seasonal allergic rhinitis. Assessment of efficacy was based on patient/caregiver recording of individual nasal symptoms (nasal congestion, rhinorrhea, itchy nose, and sneezing) on 0 to categorical severity scale (0 absent, = mild, = moderate, = 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 PATANASE, 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 to 11 Years of Age With Seasonal Allergic RhinitisTreatmentNBaselineChangeFrom BaselineDifference from PlaceboAbbreviation: CI, confidence interval. Estimate95% CIp-valuePATANASE Nasal Spray 0.6%, one spray per nostril twice daily2948.99-2.24-0.55(-0.90, -0.19)0.0015Vehicle Nasal Spray, one spray per nostril twice daily2949.09-1.70 Itchy eyes and watery eyes were evaluated as secondary endpoints in the same study but eye redness was not evaluated. Patients treated with PATANASE had significantly greater decreases in reflective symptom scores for itchy eyes and watery eyes, compared to vehicle nasal spray.

CLINICAL TRIALS EXPERIENCE SECTION.

6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.The safety data described below reflect exposure to PATANASE in 2770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of weeks to 12 months duration. PATANASE is not indicated for use in patients with perennial allergic rhinitis.The safety data from adults and adolescents are based upon 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 PATANASE two sprays per nostril twice daily. There were 1180 patients (PATANASE, 587; vehicle nasal spray, 593) that participated in efficacy and safety trials of weeks duration. There were 2840 patients (PATANASE, 1247; 3.7 pH vehicle nasal spray, 1251; 7.0 pH vehicle nasal spray, 342) that participated in long-term clinical trials of 1-year duration. The racial distribution of adult and adolescent patients receiving PATANASE was 77% white, 9% black, and 14% other. The incidence of discontinuation due to adverse reactions in these controlled clinical trials was comparable for PATANASE and vehicle nasal spray. Overall, 4.7% of the 1834 adult and adolescent patients across all studies treated with PATANASE, 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 to 11 years of age are based upon clinical trials in which 870 children with SAR (376 females and 494 males) were treated with PATANASE one or two sprays per nostril twice daily for weeks. The racial distribution of pediatric patients receiving PATANASE 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 PATANASE and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all studies treated with PATANASE 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) TrialsThere were 1180 patients 12 years of age and older (PATANASE, 587; vehicle nasal spray, 593) that participated in efficacy and safety trials of weeks duration. Table presents the most common adverse reactions (0.9% or greater in patients treated with PATANASE) that occurred more frequently in patients treated with PATANASE compared with vehicle nasal spray in the clinical trials of weeks duration.Table 1: Adverse Reactions Occurring at an Incidence of 0.9% or Greater in Controlled Clinical Trials of Weeks Duration With PATANASE in Adolescent and Adult Patients 12 Years of Age and Older With Seasonal Allergic RhinitisAdult and Adolescent Patients 12 Years and OlderAdverse ReactionPATANASEN 587Vehicle Nasal SprayN 593Abbreviation: CPK, creatine phosphokinase.Bitter taste75 (12.8%)5 (0.8%)Headache26 (4.4%)24 (4.0%)Epistaxis19 (3.2%)10 (1.7%)Pharyngolaryngeal Pain13 (2.2%)8 (1.3%)Post-nasal drip9 (1.5%)5 (0.8%)Cough8 (1.4%)3 (0.5%)Urinary tract infection7 (1.2%)3 (0.5%)CPK elevation5 (0.9%)2 (0.3%)Dry mouth5 (0.9%)1 (0.2%)Fatigue5 (0.9%)4 (0.7%)Influenza5 (0.9%)1 (0.2%)Nasopharyngitis5 (0.9%)4 (0.7%)Somnolence5 (0.9%)2 (0.3%)Throat irritation5 (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 to 11 Years of AgeThere were 1742 pediatric patients to 11 years of age (olopatadine nasal spray, 870; vehicle nasal spray, 872) with SAR that participated in clinical trials of weeks duration. Two of the studies used the investigational formulation of olopatadine nasal spray, and one of the studies used PATANASE. One study evaluated the safety of PATANASE at doses of one and two sprays per nostril twice daily in 1188 patients, in which 298 were exposed to PATANASE spray, 296 were exposed to PATANASE sprays, 297 were exposed to vehicle spray, and 297 were exposed to vehicle sprays twice daily for weeks. Table presents the most common adverse reactions (greater than 1.0% in pediatric patients to 11 years of age treated with PATANASE one spray per nostril) that occurred more frequently with PATANASE compared with vehicle nasal spray.Table 2. Adverse Reactions Occurring at an Incidence of Greater Than 1.0% in Controlled Clinical Trial of Weeks Duration With PATANASE in Pediatric Patients to 11 Years of Age With Seasonal Allergic RhinitisPediatric Patients to 11 Years of AgeAdverse ReactionPATANASE One Spray per NostrilN 298Vehicle Nasal Spray One Spray per NostrilN 297EpistaxisHeadacheUpper respiratory tract infectionBitter taste17 (5.7%)13 (4.4%)8 (2.6%)3 (1.0%)11 (3.7%)11 (3.7%)00Pyrexia4 (1.3%)3 (1.0%)Rash4 (1.3%)0There were no differences in the incidence of adverse reactions based on gender, race, or ethnicity.Long-Term (12 month) Safety TrialsIn 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 PATANASE two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). In the PATANASE 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 PATANASE and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of patients treated with PATANASE and 0.2% of patients treated with vehicle nasal spray. Nasal ulcerations occurred in 10% of patients treated with PATANASE and 9% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with PATANASE 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 patient treated with PATANASE and patient treated with vehicle nasal spray. Weight increase was reported in patients treated with PATANASE and patient treated with vehicle nasal spray. Depression or worsening of depression occurred in patients treated with PATANASE and in patients treated with vehicle nasal spray. Three patients, of whom had preexisting histories of depression, who received PATANASE were hospitalized for depression compared to none who received vehicle nasal spray.In 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 PATANASE containing povidone (not the commercially marketed formulation) and 465 patients were treated with sprays of vehicle nasal spray containing povidone. Nasal septal perforations were reported in one patient treated with the investigational formulation of PATANASE and patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated with the investigational formulation of PATANASE and 12% of patients treated with vehicle nasal spray. Somnolence was reported in patients treated with the investigational formulation of PATANASE compared to patient treated with vehicle nasal spray. Fatigue was reported in patients treated with the investigational formulation of PATANASE compared to patient treated with vehicle nasal spray.In 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 PATANASE (343 patients), 3.7 pH vehicle nasal spray (341 patients), or 7.0 pH vehicle nasal spray (342 patients). All treatments were administered as two sprays per nostril, twice daily. Overall, 5% of PATANASE 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 PATANASE, 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 patients treated with PATANASE and 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 PATANASE, 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 patient treated with PATANASE. Hyposmia and anosmia were each reported by one patient treated with PATANASE. Neither somnolence nor weight loss was reported. Depression occurred in patients treated with PATANASE, patients treated with 3.7 pH vehicle nasal spray, and patients treated with 7.0 pH vehicle nasal spray.There were no long-term clinical trials in children below 12 years of age.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. None.. None (4).

DESCRIPTION SECTION.

11 DESCRIPTION. PATANASE (olopatadine hydrochloride), 665 mcg is metered-spray solution for nasal administration. Olopatadine hydrochloride, the active component of PATANASE, is white, water-soluble crystalline powder. The chemical name for olopatadine hydrochloride is (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride. It has molecular weight of 373.88 g/mol, and its molecular formula is C21H23NO3oHCl with the following chemical structure:PATANASE contains 0.6% w/v olopatadine (base) in nonsterile aqueous solution with pH of approximately 3.7. After initial priming (5 sprays), each metered spray from the nasal applicator delivers 100 uL of the aqueous solution containing 665 mcg of olopatadine hydrochloride, which is equivalent to 600 mcg of olopatadine (base) [see Dosage Forms and Strengths (3)]. PATANASE also contains benzalkonium chloride (0.01%), dibasic sodium phosphate, edetate disodium, hydrochloric acid and/or sodium hydroxide (to adjust pH), purified water and sodium chloride.. chemical.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. For nasal use only. Recommended dosages:Adults and Adolescents >= 12 Years: Two sprays per nostril (665 mcg per spray) twice daily (2.1).Pediatric Patients to 11 Years: One spray per nostril (665 mcg per spray) twice daily (2.2).Priming Information: Prime PATANASE before initial use and when PATANASE has not been used for more than days (2.3).. Adults and Adolescents >= 12 Years: Two sprays per nostril (665 mcg per spray) twice daily (2.1).. Pediatric Patients to 11 Years: One spray per nostril (665 mcg per spray) twice daily (2.2).. Priming Information: Prime PATANASE before initial use and when PATANASE has not been used for more than days (2.3).. 2.1 Adults and Adolescents Twelve Years of Age and Older. The recommended dosage is two sprays per nostril twice daily.. 2.2 Pediatric Patients Six to Eleven Years of Age. The recommended dosage is one spray per nostril twice daily.. 2.3 Administration Information. Administer PATANASE by the nasal route only.Priming: Before initial use, prime PATANASE by releasing sprays or until fine mist appears. The correct amount of medication cannot be assured before the initial priming.Re-priming (as needed): When PATANASE has not been used for more than days, re-prime by releasing sprays. Avoid spraying PATANASE 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.

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. Nasal spray: 665 mcg olopatadine hydrochloride per spray supplied in white plastic bottle with metered-dose manual spray pump, white nasal applicator, and blue overcap.. Nasal spray: 665 mcg of olopatadine hydrochloride in each spray (3).

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Formal drug-drug interaction studies were not conducted for PATANASE. Drug interactions with inhibitors of liver enzymes are not anticipated because olopatadine is eliminated predominantly by renal excretion. Drug interactions involving P450 inhibition and plasma protein binding are also not expected [see Clinical Pharmacology (12.3)].

GERIATRIC USE SECTION.

8.5 Geriatric Use. Clinical studies of PATANASE 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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. How SuppliedPATANASE, 665 mcg is supplied in white plastic bottle with metered-dose manual spray pump, white nasal applicator and blue overcap in box of (NDC 0065-0332-30). Each trade size bottle contains 30.5 of clear, colorless liquid and will provide 240 metered sprays. After priming [see Dosage and Administration (2.3)], each spray delivers fine mist containing 665 mcg of olopatadine hydrochloride in 100 uL of formulation through the nozzle.Net content 30.5 g, 240 sprays: NDC 0065-0332-30 (trade size)StorageStore PATANASE at room temperature between 4C to 25C (39F to 77F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. PATANASE is indicated for the relief of the symptoms of seasonal allergic rhinitis (SAR) in adults and pediatric patients years of age and older.. PATANASE is an H1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis (SAR) in adults and pediatric patients years of age and older (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use).Local Nasal Effects and Other Common Adverse ReactionsInform patients that treatment with PATANASE may lead to adverse reactions, which include epistaxis and nasal ulcerations [see Warnings and Precautions (5.1)]. Other common adverse reactions reported with use of PATANASE include bitter taste, headache, and pharyngolaryngeal pain [see Adverse Reactions (6)].Somnolence and Impaired Mental AlertnessSomnolence has been reported in some patients taking PATANASE. Caution patients against engaging in hazardous occupations requiring complete mental alertness and motor coordination, such as driving or operating machinery after administration of PATANASE [see Warnings and Precautions (5.2)].Concurrent Use of Alcohol and Other Central Nervous System DepressantsAdvise patients that concurrent use of PATANASE 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 EyesInform patients to avoid spraying PATANASE in their eyes [see Dosage and Administration (2.3)].Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2021-14.

INSTRUCTIONS FOR USE SECTION.

This Instructions for Use has been approved by the U.S. Food and Drug Administration.Revised: March 2021INSTRUCTIONS FOR USEPATANASE(R) [PAT-uh-nase](olopatadine hydrochloride)nasal spray, for intranasal useThis Instructions for Use contains information on how to use PATANASE.Read this Instructions for Use that comes with PATANASE before you start using it and each time you get refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or treatment.PATANASE is for use in your nose only. Do not spray PATANASE in your eyes or mouth.Important Information You Need to Know Before Using PATANASEUse PATANASE exactly how your healthcare provider tells you to use it.Your PATANASE bottle must be shaken and primed before you use it for the first time and when you have not used it for more than days.Throw away PATANASE after 240 sprays 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.Using PATANASEStep 1. Remove the plastic cap (see Figure A).Figure AStep 2. Hold the bottle and press down on the shoulders of the nasal applicator with your forefinger and middle finger.Support the bottom of the bottle with your thumb (see Figure B). Prime the bottle by pressing and releasing the shoulders of the bottle down firmly times or until you see fine mist come out of the nasal applicator.Now your pump is primed and ready to use.If you do not use PATANASE for more than days, you will need to prime the bottle again by pressing and releasing the shoulders of the bottle down firmly times or until you see fine mist come out of the nasal applicator. Figure BStep 3. Gently blow your nose to clear your nostrils. Hold nostril closed with finger. Tilt your head down (chin toward chest) and insert the nasal applicator into nostril. Hold the bottle upright with the nasal applicator tip pointing away from the center of the nose (see Figure C). Step 4. Breathe in gently through your nose. While breathing in, press firmly and quickly on the nasal applicator shoulders to release the spray into your nostril (see Figure C). Step 5. Breathe out through your mouth. Do not tilt your head back or blow your nose right after using PATANASE. This may cause you to get bitter taste in your mouth. Step 6. Repeat Steps through above to deliver spray in your other nostril. Step 7. If your healthcare provider tells you to use sprays in each nostril, repeat Steps through for the second spray in each nostril. Figure CStep 8. Wipe the nasal applicator with clean tissue and replace the plastic cap (see Figure D).Figure DCleaning the PATANASE nasal applicatorStep 9. To clean the nasal applicator, remove the plastic cap (see Figure E). If the nasal applicator becomes clogged, do not try to clear it using pointed object.Figure EStep 10. Gently pull the nasal applicator up to remove it from the bottle (see Figure F).Figure FStep 11. With the nasal applicator pointing downwards, wash it by running warm tap water into the nasal applicator for about minute (see Figure G). Step 12. Shake the nasal applicator to remove any water and put the nasal applicator back on the bottle. Step 13. Prime the bottle again by pressing the shoulders of the bottle down firmly and releasing the shoulders times or until you see fine mist come out of the white nasal applicator. Repeat Steps 11 and 12 above if the nasal applicator is still clogged.Figure GHow should store PATANASEStore PATANASE at room temperature between 39F to 77F (4C to 25C).Do not use PATANASE after the expiration date on the label or box.Keep PATANASE and all medicines out of the reach of children.For more information about PATANASE, call 1-888-669-6682.Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936(C) NovartisT2021-16. Use PATANASE exactly how your healthcare provider tells you to use it.. Your PATANASE bottle must be shaken and primed before you use it for the first time and when you have not used it for more than days.. Throw away PATANASE after 240 sprays 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.. Support the bottom of the bottle with your thumb (see Figure B). Prime the bottle by pressing and releasing the shoulders of the bottle down firmly times or until you see fine mist come out of the nasal applicator.. Now your pump is primed and ready to use.. If you do not use PATANASE for more than days, you will need to prime the bottle again by pressing and releasing the shoulders of the bottle down firmly times or until you see fine mist come out of the nasal applicator.. Store PATANASE at room temperature between 39F to 77F (4C to 25C).. Do not use PATANASE after the expiration date on the label or box.. Figure A. Figure B. Figure C. Figure D. Figure E. Figure F. Figure G.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for PATANASE and any potential adverse effects on the breastfed infant from PATANASE or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Olopatadine is histamine H1 receptor antagonist. The antihistaminic activity of olopatadine has been documented in isolated tissues, animal models, and humans.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. CarcinogenesisOlopatadine demonstrated no tumorigenic potential in mice at oral doses up to 500 mg/kg/day (approximately 460 times the MRHDID on mg/m2 basis) for 78 weeks or in rats at oral doses up to 200 mg/kg/day (approximately 370 times the MRHDID on mg/m2 basis) for 104 weeks.MutagenesisNo 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.Impairment of FertilityOlopatadine administered at an oral dose of 400 mg/kg/day, (approximately 730 times the MRHDID for adults on an mg/m2 basis) produced toxicity in male and female rats, and resulted in decrease in the fertility index and reduced implantation rate. No effects on reproductive function were observed at 50 mg/kg/day (approximately 90 times the MRHDID on mg/m2 basis).

OVERDOSAGE SECTION.

10 OVERDOSAGE. Symptoms of antihistamine overdose may include drowsiness in both adults and children. Agitation and restlessness followed by drowsiness may also occur in children. There is no known specific antidote to PATANASE. Should overdose occur, symptomatic or supportive treatment is recommended, taking into account any concomitantly ingested medications.For additional information about overdose treatment, call poison control center (1-800-222-1222).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL. FOR INTRANASAL USE ONLYRx OnlyNDC 0065-0332-30Patanase(R) (olopatadine hydrochloride)Nasal Spray, 665 mcg240 Metered SpraysNet Fill Weight 30.5g. carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of PATANASE for the relief of symptoms of SAR have been established in pediatric patients aged years and older.The safety and effectiveness of PATANASE in pediatric patients to 11 years of age are supported by 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 PATANASE at doses of one and two sprays per nostril twice daily in 1188 patients, of which 298 patients were exposed to PATANASE spray, and 297 patients were exposed to vehicle spray. In this study, the incidence of epistaxis with PATANASE use was 5.7% [see Adverse Reactions (6.1), Clinical Studies (14)].The safety and effectiveness of PATANASE in pediatric patients aged 12 years and older are supported by randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials of weeks duration in adult and adolescent patients [see Clinical Studies (14)]. In these studies, the incidence of epistaxis with PATANASE use in 587 patients was 3.2% [see Adverse Reactions (6.1)].The safety and effectiveness of PATANASE have not been established in pediatric patients under years of age.The safety of PATANASE at dose of one spray per nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 pediatric patients to years of age with allergic rhinitis. In this trial, 66 patients were exposed to PATANASE. 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 to years of age than to 11 year old age group (< 1%).

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Cardiac ElectrophysiologyIn placebo-controlled cardiovascular safety study, 32 healthy volunteers received 20 mg oral solution of olopatadine twice daily for 14 days (8-fold greater daily dose than the recommended daily nasal dose). The mean QTcF (QT corrected by Fridericias correction method for heart rate) change from baseline was -2.7 msec and -3.8 msec for olopatadine, and placebo, respectively. In this study, subjects treated with olopatadine had QTcF change from baseline of 30-60 msec, subject had QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. Eight subjects treated with placebo had QTcF change from baseline of 30-60 msec, no subjects had QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. In 12-month study in 429 perennial allergic rhinitis patients treated with PATANASE two sprays per nostril twice daily, no evidence of any effect of olopatadine hydrochloride on QT prolongation was observed.

PHARMACOKINETICS SECTION.

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 large dose range.AbsorptionHealthy Subjects: Olopatadine was absorbed with individual peak plasma concentrations observed between 30 minutes and hour after twice daily intranasal administration of PATANASE. The mean (+- SD) steady-state peak plasma concentration (Cmax) of olopatadine was 16.0 +- 8.99 ng/mL. Systemic exposure as indexed by area under the curve (AUC0-12) 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 PATANASE was about 1.3.Seasonal Allergic Rhinitis Patients: Systemic exposure of olopatadine in SAR patients after twice daily intranasal administration of PATANASE was comparable to that observed in healthy subjects. Olopatadine was absorbed with peak plasma concentrations observed between 15 minutes and hours. The mean steady-state Cmax was 23.3 +- 6.2 ng/mL and AUC0-12 averaged 78.0 +- 13.9 ng.h/mL.DistributionThe 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.EliminationThe plasma elimination half-life of olopatadine is to 12 hours. Olopatadine is mainly eliminated through urinary excretion. Approximately 70% of [14C] 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.MetabolismOlopatadine is not extensively metabolized. Based on plasma metabolite profiles following oral administration of [14C] 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 PopulationsPatients with Hepatic ImpairmentNo specific pharmacokinetic study examining the effect of hepatic impairment was conducted. Since metabolism of olopatadine is minor route of elimination, no adjustment of the dosing regimen of PATANASE is warranted in patients with hepatic impairment.Patients with Renal ImpairmentThe mean Cmax 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 AUC0-12 was 2-fold higher in patients with severe impairment (creatinine clearance 30 mL/min/1.73 m2). 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 PATANASE is warranted in patients with renal impairment.Male and Female PatientsThe mean systemic exposure (Cmax and AUC0-12) 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 GroupsThe effects of race on olopatadine pharmacokinetics have not been adequately investigated.Pediatric Patients to 11 Years of AgeThe systemic pharmacokinetics of olopatadine, olopatadine N-oxide and N-desmethyl olopatadine in patients through 11 years of age were characterized using data from 42 pediatric patients administered PATANASE, one spray per nostril twice daily for minimum of 14 days. The mean Cmax (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 Cmax and AUC0-12 of olopatadine N-oxide were comparable to that observed in adults. The Cmax and AUC0-12 of N-desmethyl olopatadine are approximately 18% and 37% higher than that observed in adults, respectively.Pediatric Patients to Years of AgeThe systemic pharmacokinetics of olopatadine, olopatadine N-oxide, and N-desmethyl olopatadine were characterized using population pharmacokinetic methods applied to sparse data (approximately samples per patient) obtained from 66 pediatric patients (2 to less than years of age) administered one-half the recommended adult dose (one spray per nostril) of PATANASE twice daily for minimum of 14 days. The mean Cmax and AUC0-12 of olopatadine were 13.4 +- 4.6 ng/mL and 75.0+- 26.4 ng.h/mL respectively. The mean Cmax and AUC0-12 of olopatadine N-oxide and N-desmethyl olopatadine were similar to that of patients to 11 years of age.Drug Interaction StudiesDrug 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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryPublished data from postmarketing experience with antihistamines, with similar mechanism of action to PATANASE, have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are no published human data specific to PATANASE. In animal reproductive studies, oral administration of olopatadine hydrochloride to pregnant rats and rabbits caused decrease in the number of live fetuses at maternal doses approximately 110 and 1460 times the maximum recommended human daily intranasal dose (MRHDID) on mg/m2 basis, respectively (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.DataAnimal DataIn an oral embryo-fetal development study, pregnant rabbits were dosed throughout the period of organogenesis at doses up to 400 mg/kg/day. decrease in the number of live fetuses was observed at 400 mg/kg/day (1460 times the MRHDID, on mg/m2 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 mg/m2 basis). Olopatadine produced cleft palate at 60 mg/kg/day (approximately 110 times the MRHDID on mg/m2 basis) and decreased embryo-fetal viability and reduced fetal weight in rats at 600 mg/kg/day (approximately 1100 times the MRHDID on mg/m2 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 mg/m2 basis) and reduced body weight gain in pups at mg/kg/day (approximately times the MRHDID on mg/m2 basis). These effects appeared attributable to exposure of pups via the milk as demonstrated in 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.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: March 2021PATIENT INFORMATIONPATANASE(R) (PAT-uh-nase)(olopatadine hydrochloride)nasal spray, for intranasal useWhat is PATANASEPATANASE is prescription nasal spray that contains an antihistamine. PATANASE is used to treat seasonal allergy symptoms in adults and children years of age and older. It is not known if PATANASE is safe and effective in children under years of age.Before using PATANASE, tell your healthcare provider about all of your medical conditions, including if you:have nose problems, such as nose bleeds, or sores in the nose.are pregnant or planning to become pregnant. It is not known if PATANASE will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if PATANASE passes into your breast milk. You and your healthcare provider should decide if you will use PATANASE 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.PATANASE and other medicines may affect each other and cause side effects.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider or pharmacist when you get new medicine.How should use PATANASESee the Instructions for Use at the end of this Patient Information leaflet for information about the right way to use PATANASE.PATANASE is for use in your nose only. Do not spray it in your eyes or mouth. Use PATANASE 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 PATANASE, call your healthcare provider or pharmacist right away.Throw away PATANASE 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 avoid while using PATANASEPATANASE can cause sleepiness or drowsiness. Do not drive, operate machinery, or do anything that needs you to be alert until you know how PATANASE affects you.Do not drink alcohol or take any medicines that may cause you to feel sleepy while using PATANASE. It may make your sleepiness worse.What are the possible side effects of PATANASEPATANASE may cause serious side effects, including:nosebleeds.sores in the nose.hole in the cartilage between the nose (nasal septum perforation). whistling sound when you breathe may be symptom of nasal septum perforation.sleepiness or drowsiness.The most common side effects of PATANASE in people 12 years of age and older include:bad or bitter tasteheadachethroat painnose congestioncoughurinary tract infectionThe most common side effects of PATANASE in people to 11 years of age include:headacheupper respiratory tract infectionbad or bitter tastefeverrashTell 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 PATANASE. 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 store PATANASEStore PATANASE at room temperature between 39F to 77F (4C to 25C).Do not use your PATANASE after the expiration date on the label or box.Keep PATANASE and all medicines out of the reach of children.General information about PATANASE.Medicines are sometimes prescribed for conditions that are not mentioned in the Patient Information leaflet. Do not use PATANASE for condition for which it was not prescribed. Do not give PATANASE 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 PATANASE that is written for health professionals.What are the ingredients in PATANASEActive 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. Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936 (C) Novartis For more information, call 1-888-669-6682.T2021-15. have nose problems, such as nose bleeds, or sores in the nose.. are pregnant or planning to become pregnant. It is not known if PATANASE will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if PATANASE passes into your breast milk. You and your healthcare provider should decide if you will use PATANASE if you plan to breastfeed.. See the Instructions for Use at the end of this Patient Information leaflet for information about the right way to use PATANASE.. PATANASE is for use in your nose only. Do not spray it in your eyes or mouth. Use PATANASE 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 PATANASE, call your healthcare provider or pharmacist right away.. Throw away PATANASE 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.. PATANASE can cause sleepiness or drowsiness. Do not drive, operate machinery, or do anything that needs you to be alert until you know how PATANASE affects you.. Do not drink alcohol or take any medicines that may cause you to feel sleepy while using PATANASE. It may make your sleepiness worse.. nosebleeds.. sores in the nose.. hole in the cartilage between the nose (nasal septum perforation). whistling sound when you breathe may be symptom of nasal septum perforation.. sleepiness or drowsiness.. bad or bitter taste. headache. throat pain. nose congestion. cough. urinary tract infection. headache. upper respiratory tract infection. bad or bitter taste. fever. rash. Store PATANASE at room temperature between 39F to 77F (4C to 25C).. Do not use your PATANASE after the expiration date on the label or box.

SPL UNCLASSIFIED SECTION.

2.1 Adults and Adolescents Twelve Years of Age and Older. The recommended dosage is two sprays per nostril twice daily.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryPublished data from postmarketing experience with antihistamines, with similar mechanism of action to PATANASE, have not identified drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are no published human data specific to PATANASE. In animal reproductive studies, oral administration of olopatadine hydrochloride to pregnant rats and rabbits caused decrease in the number of live fetuses at maternal doses approximately 110 and 1460 times the maximum recommended human daily intranasal dose (MRHDID) on mg/m2 basis, respectively (see Data).The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4%, and 15% to 20%, respectively.DataAnimal DataIn an oral embryo-fetal development study, pregnant rabbits were dosed throughout the period of organogenesis at doses up to 400 mg/kg/day. decrease in the number of live fetuses was observed at 400 mg/kg/day (1460 times the MRHDID, on mg/m2 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 mg/m2 basis). Olopatadine produced cleft palate at 60 mg/kg/day (approximately 110 times the MRHDID on mg/m2 basis) and decreased embryo-fetal viability and reduced fetal weight in rats at 600 mg/kg/day (approximately 1100 times the MRHDID on mg/m2 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 mg/m2 basis) and reduced body weight gain in pups at mg/kg/day (approximately times the MRHDID on mg/m2 basis). These effects appeared attributable to exposure of pups via the milk as demonstrated in 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 SummaryThere 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 mothers clinical need for PATANASE and any potential adverse effects on the breastfed infant from PATANASE or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of PATANASE for the relief of symptoms of SAR have been established in pediatric patients aged years and older.The safety and effectiveness of PATANASE in pediatric patients to 11 years of age are supported by 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 PATANASE at doses of one and two sprays per nostril twice daily in 1188 patients, of which 298 patients were exposed to PATANASE spray, and 297 patients were exposed to vehicle spray. In this study, the incidence of epistaxis with PATANASE use was 5.7% [see Adverse Reactions (6.1), Clinical Studies (14)].The safety and effectiveness of PATANASE in pediatric patients aged 12 years and older are supported by randomized, double blind, parallel group, multicenter, placebo-controlled clinical trials of weeks duration in adult and adolescent patients [see Clinical Studies (14)]. In these studies, the incidence of epistaxis with PATANASE use in 587 patients was 3.2% [see Adverse Reactions (6.1)].The safety and effectiveness of PATANASE have not been established in pediatric patients under years of age.The safety of PATANASE at dose of one spray per nostril twice daily was evaluated in one 2-week vehicle-controlled study in 132 pediatric patients to years of age with allergic rhinitis. In this trial, 66 patients were exposed to PATANASE. 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 to years of age than to 11 year old age group (< 1%).. 8.5 Geriatric Use. Clinical studies of PATANASE 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Epistaxis, Nasal Ulceration, and Nasal Septal Perforation: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue if ulcerations or perforations occur. Avoid use in patients with nasal disease other than allergic rhinitis (5.1).Avoid engaging in hazardous occupations requiring complete mental alertness and coordination, such as driving or operating machinery when taking PATANASE (5.2).Avoid concurrent use of alcohol or other central nervous system depressants with PATANASE (5.2).. Epistaxis, Nasal Ulceration, and Nasal Septal Perforation: Monitor patients periodically for signs of adverse effects on the nasal mucosa. Discontinue if ulcerations or perforations occur. Avoid use in patients with nasal disease other than allergic rhinitis (5.1).. Avoid engaging in hazardous occupations requiring complete mental alertness and coordination, such as driving or operating machinery when taking PATANASE (5.2).. Avoid concurrent use of alcohol or other central nervous system depressants with PATANASE (5.2).. 5.1 Local Nasal Effects. Epistaxis and Nasal UlcerationIn placebo-controlled clinical trials (vehicle nasal spray) of weeks to 12 months duration, epistaxis and nasal ulcerations were reported [see Adverse Reactions (6.1)].Nasal Septal PerforationThree placebo-controlled long term (12 months) safety trials (vehicle nasal spray) were conducted. In the first safety trial, patients were treated with an investigational formulation of PATANASE containing povidone (not the commercially marketed formulation) or vehicle nasal spray containing povidone. Nasal septal perforations were reported in one patient treated with the investigational formulation of PATANASE and patients treated with the vehicle nasal spray. In the second safety trial with PATANASE, 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 nasal septal perforation [see Adverse Reactions (6.1)].Before starting PATANASE, conduct 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 PATANASE 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 PATANASE [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 PATANASE. Concurrent use of PATANASE 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.