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.

3 DOSAGE FORMS AND STRENGTHS Olopatadine HCl nasal spray, 665 mcg is a clear, colorless solution packaged in a white plastic bottle fitted with a metered-dose spray pump, a white colored dust cover and white safety clip. Each spray (100 microliters) delivers 665 mcg of olopatadine hydrochloride, USP. Nasal spray: 665 mcg of olopatadine hydrochloride, USP in each spray (3) .

4 CONTRAINDICATIONS None. None (4) .

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 Dur …

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) ] .

8 USE IN SPECIFIC POPULATIONS 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. 8.2 Lactation Risk Summary There are no data on the presence of olopatadine in human milk, the effects on the breastfed infant, or the effects on milk production. Although orally administered olopatadine is present in rat milk, there is no information about nasally administered olopatadine. It is not known whether topical nasal administration could result in sufficient systemic absorption to produce detectable quantities in human breast milk. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for olopatadine HCl and any potential adverse effects on the breast fed infant from olopatadine HCl or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of olopatadine HCl for the relief of symptoms of seasonal allergic rhinitis have been established in pediatric patients aged 6 years and older. The safety and effectiveness of olopatadine HCl in pediatric patients 6 to 11 years of age are supported by 3 vehicle-controlled 2-week studies in 870 patients [see Adverse Reactions (6.1) ] . Doses studied included one and two sprays per nostril twice daily. One of these studies evaluated the safety of olopatadine HCl at doses of one and two sprays per nostril twice daily in 1,188 patients, of which 298 patients were exposed to olopatadine HCl 1 spray, and 297 patients were exposed to vehicle 1 spray. In this study, the incidence of epistaxis with olopatad …

12.1 Mechanism of Action Olopatadine is a histamine H 1 receptor antagonist. The antihistaminic activity of olopatadine has been documented in isolated tissues, animal models, and humans.

11 DESCRIPTION Olopatadine HCl nasal spray, 665 mcg is a metered-spray solution for nasal administration. Olopatadine hydrochloride USP, the active component of olopatadine HCl nasal spray, 665 mcg, is a white, water-soluble crystalline powder. The chemical name for olopatadine hydrochloride, USP is (Z)-11-[3-(dimethylamino)propylidene]-6,11-dihydrodibenz [b,e]oxepin-2-acetic acid hydrochloride. It has a molecular weight of 373.88 g/mol, and its molecular formula is C 21 H 23 NO 3 •HCl with the following chemical structure: Olopatadine HCl nasal spray, 665 mcg contains 0.6% w/v olopatadine (base) in a nonsterile aqueous solution with pH of approximately 3.7. After initial priming (5 sprays), each metered spray from the nasal applicator delivers 100 microliters of the aqueous solution containing 665 mcg of olopatadine hydrochloride USP, which is equivalent to 600 mcg of olopatadine (base) [see Dosage Forms and Strengths (3) ] . Olopatadine HCl nasal spray also contains benzalkonium chloride (0.01%), dibasic sodium phosphate (anhydrous), edetate disodium, sodium chloride, hydrochloric acid and/or sodium hydroxide (to adjust pH), and purified water. Structural Formula

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 olopatadine HCl. Should overdose occur, symptomatic or supportive treatment is recommended, taking into account any concomitantly ingested medications. For additional information about overdose treatment, call a poison control center (1-800-222-1222).

16 HOW SUPPLIED/STORAGE AND HANDLING How Supplied Olopatadine HCl nasal spray, 665 mcg is supplied in a white plastic bottle with nasal applicator, fitted with a metered-dose manual spray pump, a white colored dust cover and white safety clip in a box of 1 (NDC 65162-890-23). Each trade size bottle contains 30.5 g of clear, colorless liquid and will provide 240 metered sprays. After priming [see Dosage and Administration (2.3) ] , each spray delivers a fine mist containing 665 mcg of olopatadine hydrochloride, USP in 100 microliters of formulation through the nozzle. Net content 30.5 g, 240 sprays: NDC 65162-890-23 (trade size) Storage Store olopatadine HCl nasal spray at room temperature between 4°C to 25°C (39°F to 77°F).