Olopatadine Hydrochloride

1 INDICATIONS AND USAGE Olopatadine hydrochloride (HCl) nasal spray is indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older. Olopatadine hydrochloride (HCl) nasal spray is an H 1 receptor antagonist indicated for the relief of the symptoms of seasonal allergic rhinitis in adults and pediatric patients 6 years of age and older (1) .

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 6 to 11 Years: One spray per nostril (665 mcg per spray) twice daily (2.2) . Priming Information: Prime olopatadine HCl nasal spray before initial use and when olopatadine HCl nasal spray has not been used for more than 7 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 olopatadine HCl nasal spray by the nasal route only. Priming: Before initial use, prime olopatadine HCl nasal spray by releasing 5 sprays or until a fine mist appears. The correct amount of medication cannot be assured before the initial priming. Re-priming (as needed): When olopatadine HCl nasal spray has not been used for more than 7 days, re-prime by releasing 2 sprays. Avoid spraying olopatadine HCl 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.

4 CONTRAINDICATIONS None. None (4) .

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 olopatadine HCl (5.2) . Avoid concurrent use of alcohol or other central nervous system depressants with olopatadine HCl (5.2) . 5.1 Local Nasal Effects Epistaxis and Nasal Ulceration In placebo-controlled clinical trials (vehicle nasal spray) of 2 weeks to 12 months duration, epistaxis and nasal ulcerations were reported [see Adverse Reactions (6.1) ] . Nasal Septal Perforation Three 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 olopatadine HCl 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 HCl and 2 patients treated with the vehicle nasal spray. In the second safety trial with olopatadine HCl, 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 HCl, 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 HCl 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 HCl [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 HCl. Concurrent use of olopatadine HCl 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.

7 DRUG INTERACTIONS Formal drug-drug interaction studies were not conducted for olopatadine HCl. 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) ] .

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) ] 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 6 to 11 years of age (6.1) . To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals, at 1-877-835-5472 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 a 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 olopatadine HCl in 2,770 patients with seasonal or perennial allergic rhinitis in 10 controlled clinical trials of 2 weeks to 12 months duration. Olopatadine HCl 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 1,834 patients with seasonal or perennial allergic rhinitis (652 males and 1,182 females) 12 years of age and older were treated with olopatadine HCl two sprays per nostril twice daily. There were 1,180 patients (olopatadine HCl, 587; vehicle nasal spray, 593) that participated in 3 efficacy and safety trials of 2 weeks duration. There were 2,840 patients (olopatadine HCl, 1,247; 3.7 pH vehicle nasal spray, 1,251; 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 HCl 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 HCl and vehicle nasal spray. Overall, 4.7% of the 1,834 adult and adolescent patients across all 6 studies treated with olopatadine HCl, 3.5% of the 1,844 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 HCl one or two sprays per nostril twice daily for 2 weeks. The racial distribution of pediatric patients receiving olopatadine HCl 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 HCl and vehicle nasal spray. Overall, 1.4% of the 870 pediatric patients across all 3 studies treated with olopatadine HCl 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 1,180 patients 12 years of age and older (olopatadine HCl, 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 HCl) that occurred more frequently in patients treated with olopatadine HCl 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 HCl 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 HCl 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 1,742 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 HCl. One study evaluated the safety of olopatadine HCl at doses of one and two sprays per nostril twice daily in 1,188 patients, in which 298 were exposed to olopatadine HCl 1 spray, 296 were exposed to olopatadine HCl 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 HCl one spray per nostril) that occurred more frequently with olopatadine HCl 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 HCl in Pediatric Patients 6 to 11 Years of Age With Seasonal Allergic Rhinitis Adverse Reaction Pediatric Patients 6 to 11 Years of Age Olopatadine HCl One Spray per Nostril N = 298 Vehicle Nasal Spray One Spray per Nostril N = 297 Epistaxis 17 (5.7%) 11 (3.7%) Headache 13 (4.4%) 11 (3.7%) Upper respiratory tract infection 8 (2.6%) 0 Bitter taste 3 (1.0%) 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 HCl two sprays per nostril twice daily (445 patients) or vehicle nasal spray (445 patients). In the olopatadine HCl 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 HCl and 28% in patients treated with vehicle nasal spray. Epistaxis resulted in discontinuation of 0.9% of patients treated with olopatadine HCl and 0.2% of patients treated with vehicle nasal spray. Nasal ulcerations occurred in 10% of patients treated with olopatadine HCl and 9% of patients treated with vehicle nasal spray. Nasal ulcerations resulted in discontinuation of 0.4% of patients treated with olopatadine HCl 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 HCl and 1 patient treated with vehicle nasal spray. Weight increase was reported in 6 patients treated with olopatadine HCl and 1 patient treated with vehicle nasal spray. Depression or worsening of depression occurred in 9 patients treated with olopatadine HCl and in 5 patients treated with vehicle nasal spray. Three patients, 2 of whom had preexisting histories of depression, who received olopatadine HCl 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 HCl 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 HCl and 2 patients treated with the vehicle nasal spray. Epistaxis was reported in 19% of patients treated with the investigational formulation of olopatadine HCl and 12% of patients treated with vehicle nasal spray. Somnolence was reported in 3 patients treated with the investigational formulation of olopatadine HCl compared to 1 patient treated with vehicle nasal spray. Fatigue was reported in 5 patients treated with the investigational formulation of olopatadine HCl 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, 1,026 patients 12 years of age and older with perennial allergic rhinitis were randomized to treatment with olopatadine HCl (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 HCl 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 HCl, 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 HCl 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 HCl, 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 HCl. Hyposmia and anosmia were each reported by one patient treated with olopatadine HCl. Neither somnolence nor weight loss was reported. Depression occurred in 3 patients treated with olopatadine HCl, 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 HCl, 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 HCl.

8.1 Pregnancy Risk Summary Published data from postmarketing experience with antihistamines, with similar mechanism of action to olopatadine HCl, have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. However, there are no published human data specific to olopatadine HCl. In animal reproductive studies, oral administration of olopatadine hydrochloride to pregnant rats and rabbits caused a decrease in the number of live fetuses at maternal doses approximately 110 and 1,460 times the maximum recommended human daily intranasal dose (MRHDID) on a mg/m 2 basis, respectively ( see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a 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. 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 (1,460 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 1,100 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 1,100 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.