Ryaltris

1 INDICATIONS AND USAGE RYALTRIS is indicated for the treatment of symptoms of seasonal allergic rhinitis in adult and pediatric patients 12 years of age and older. RYALTRIS is a combination of olopatadine, a histamine-1 (H1)-receptor inhibitor, and mometasone furoate, a corticosteroid, indicated for the treatment of symptoms of seasonal allergic rhinitis in adult and pediatric patients 12 years of age and older. ( 1 )

2 DOSAGE AND ADMINISTRATION For nasal use only. The recommended dosage of RYALTRIS is 2 sprays (2 sprays deliver a total of 1,330 mcg of olopatadine hydrochloride and 50 mcg of mometasone furoate) in each nostril twice daily. • Shake the bottle well before each use. • Prime RYALTRIS before initial use by releasing 6 sprays or until a fine mist appears. When RYALTRIS has not been used for 14 or more days, re-prime by releasing 2 sprays or until a fine mist appears. • Avoid spraying RYALTRIS into the eyes or mouth. • For nasal use only ( 2 ) • Recommended dosage: 2 sprays in each nostril twice daily ( 2 ) • Prime before initial use by releasing 6 sprays or until a fine mist appears and when it has not been used for 14 or more days by releasing 2 sprays or until a fine mist appears. ( 2 )

4 CONTRAINDICATIONS RYALTRIS is contraindicated in patients with known hypersensitivity to any ingredients of RYALTRIS. Hypersensitivity reactions, including wheezing, has occurred after nasal administration of mometasone furoate [see Warnings and Precautions ( 5.4 )]. Patients with known hypersensitivity to any ingredients of RYALTRIS, including mometasone furoate. ( 4 )

5 WARNINGS AND PRECAUTIONS • Epistaxis, nasal ulcerations, nasal septal perforations, impaired wound healing, and Candida albicans infection: Monitor patients periodically for signs of adverse reactions on the nasal mucosa. ( 5.1 ) • Somnolence: Avoid engaging in hazardous occupations requiring complete mental alertness and motor coordination such as driving or operating machinery when taking RYALTRIS. ( 5.2 ) • Avoid concurrent use of alcohol or other central nervous system (CNS) depressants with RYALTRIS because additional reductions in alertness and additional impairment of CNS performance may occur. ( 5.2 ) • Glaucoma and cataracts: Monitor patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. ( 5.3 ) • Hypersensitivity Reactions: Hypersensitivity reactions can occur with RYALTRIS. Hypersensitivity reactions including wheezing, have occurred after the nasal administration of mometasone furoate. Discontinue RYALTRIS if such reactions occur. ( 5.4 ) • Immunosuppression and Risk of Infections: Potential worsening of existing tuberculosis; fungal, bacterial, viral, or parasitic infections; or ocular herpes simplex. More serious or even fatal course of chickenpox or measles in susceptible patients: Use caution in patients with the above because of the potential for worsening of these infections. ( 5.5 ) • Hypercorticism and adrenal suppression with misuse or use of higher-than-recommended dosages or at the regular dosage in susceptible patients at risk for such effects ( 5.6 ) • Potential reduction in growth velocity in children: Routinely monitor the growth in pediatric patients receiving RYALTRIS. ( 5.7 , 8.4 ) 5.1 Local Nasal Adverse Reactions Epistaxis Epistaxis was observed in 1% of patients treated with RYALTRIS and 0.6% of patients who received placebo in 2-week studies in patients with seasonal allergic rhinitis [see Adverse Reactions ( 6.1 )]. Nasal Ulceration and Nasal Septal Perforation Instances of nasal ulceration and nasal septal perforation have occurred in patients following the nasal application of antihistamines such as RYALTRIS. Monitor patients periodically for signs of adverse effects on the nasal mucosa. Impaired Nasal Wound Healing Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal septal ulcers, nasal surgery, or nasal trauma should avoid use of RYALTRIS until healing has occurred. Local Candida Infection Localized infections of the nose and pharynx with Candida albicans have occurred from nasal administration of mometasone furoate. When such an infection occurs, discontinue RYALTRIS and institute appropriate local or systemic therapy. Patients using RYALTRIS over several months or longer should be examined periodically for evidence of Candida infection. 5.2 Somnolence and Impaired Mental Alertness Patients should be cautioned against engaging in hazardous occupations requiring complete mental alertness and motor coordination, such as operating machinery or driving a motor vehicle, after administration of RYALTRIS. Concurrent use of RYALTRIS with alcohol or other central nervous system (CNS) depressants should be avoided because additional reductions in alertness and additional impairment of CNS performance may occur. Somnolence was reported in 0.3% of patients treated with RYALTRIS and none of the patients who received placebo in 2-week studies in patients with seasonal allergic rhinitis [see Adverse Reactions ( 6.1 )] . 5.3 Glaucoma and Cataracts Nasal and inhaled corticosteroids including RYALTRIS can result in the development of glaucoma and/or cataracts. Therefore, close monitoring is warranted in patients with a change in vision or with a history of increased intraocular pressure, glaucoma, and/or cataracts. 5.4 Hypersensitivity Reactions Hypersensitivity reactions can occur with RYALTRIS. Hypersensitivity reactions including wheezing, have occurred after the nasal administration of mometasone furoate. Discontinue RYALTRIS if such reactions occur [see Contraindications ( 4 )] . 5.5 Immunosuppression and Risk of Infections Persons who are using drugs that suppress the immune system, such as corticosteroids, including RYALTRIS, are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, can have a more serious or even fatal course in susceptible children or adults using corticosteroids. In children or adults who have not had these diseases or been properly immunized, particular care should be taken to avoid exposure. How the dose, route, and duration of corticosteroid administration affect the risk of developing a disseminated infection is not known. The safety and effectiveness of RYALTRIS have not been established in pediatric patients less than 12 years of age and RYALTRIS is not indicated for use in this population. The contribution of the underlying disease and/or prior corticosteroid treatment to the risk is also not known. If exposed to chickenpox, prophylaxis with varicella zoster immune globulin (VZIG) may be indicated. If exposed to measles, prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated (see the respective Prescribing Information for VZIG and IG). If chickenpox develops, treatment with antiviral agents may be considered. Corticosteroids should be used with caution, if at all, in patients with active or quiescent tuberculous infections of the respiratory tract, untreated local or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex because of the potential for worsening of these infections. 5.6 Hypercorticism and Adrenal Suppression Hypercorticism and adrenal suppression may occur when nasal corticosteroids, including RYALTRIS, are misused by taking higher-than-recommended dosages [see Dosage and Administration ( 2 )] or in patients at risk for such effects. 5.7 Effect on Growth Nasal corticosteroids, including RYALTRIS, may cause a reduction in growth velocity when administered to pediatric patients. The safety and effectiveness of RYALTRIS have not been established in pediatric patients less than 12 years of age and RYALTRIS is not indicated for use in this population. Routinely monitor the growth of pediatric patients receiving RYALTRIS [see Use in Specific Populations ( 8.4 )] .

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been performed with RYALTRIS. The drug interactions of the combination are expected to reflect those of the individual components [see Clinical Pharmacology ( 12.3 )] . 7.1 Central Nervous System Depressants Concurrent use of RYALTRIS with alcohol or other central nervous system depressants should be avoided because somnolence and impairment of central nervous system performance may occur [see Warnings and Precautions ( 5.2 )] . 7.2 Inhibitors of Cytochrome P450 3A4 Studies have shown that mometasone furoate, a component of RYALTRIS, is primarily and extensively metabolized to multiple metabolites. In vitro studies have confirmed the primary role of cytochrome P450 (CYP) 3A4 in the metabolism of this compound. Concomitant administration of CYP3A4 inhibitors may inhibit the metabolism of, and increase the mometasone furoate plasma concentration and potentially increase the risk for adverse reactions. Caution should be exercised when considering the coadministration of RYALTRIS with strong CYP3A4 inhibitors [see Clinical Pharmacology ( 12.3 )] .

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in labeling: • Local Nasal Adverse Reactions [see Warnings and Precautions ( 5.1 )] • Somnolence and Impaired Mental Alertness [see Warnings and Precautions ( 5.2 )] • Glaucoma and Cataracts [see Warnings and Precautions ( 5.3 )] • Hypersensitivity Reactions [see Warnings and Precautions ( 5.4 )] • Immunosuppression and Risk of Infections [see Warnings and Precautions ( 5.5 )] • Hypercorticism and Adrenal Suppression [see Warnings and Precautions ( 5.6 ), Use in Specific Populations ( 8.4 )] • Effect on Growth [see Warnings and Precautions ( 5.7 )] The most common adverse reactions (≥1% incidence) are dysgeusia, epistaxis, and nasal discomfort. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Glenmark Pharmaceuticals Inc., USA at 1 (888) 721-7115 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared with rates in the clinical studies of another drug and may not reflect the rates observed in practice. Adults and Pediatric Patients 12 Years of Age and Older The pooled RYALTRIS safety population reflects exposure to RYALTRIS at 2 sprays (2 sprays deliver a total of 1,330 mcg of olopatadine hydrochloride and 50 mcg of mometasone furoate) in each nostril twice daily in a total of 1189 patients from Studies 1 and 2 [see Clinical Studies (14)] and from three additional placebo and/or active-controlled studies in patients with allergic rhinitis. One placebo controlled study was a 52-week safety study. In this study, 393 patients were exposed to RYALTRIS for one year, and no new safety signals were observed. The RYALTRIS safety population described below reflects exposure to RYALTRIS at 2 sprays (2 sprays deliver a total of 1,330 mcg of olopatadine hydrochloride and 50 mcg of mometasone furoate) in each nostril twice daily for two weeks duration in a total of 789 patients, including 596 patients from Studies 1 and 2 [see Clinical Studies (14)], and 36 and 157 from two additional placebo and active-controlled studies in patients with seasonal allergic rhinitis. The demographics of the RYALTRIS-treated patients were 12 to 81 years of age (mean age of 40 years; 67% female; 81% White, 15% Black/African American and 3% Other). Table 1 lists adverse reactions from the safety population reported with frequencies ≥1% and more frequently than placebo in patients treated with RYALTRIS. Somnolence was reported in <1% (2 of 789) of patients treated with RYALTRIS and no patients treated with placebo. Table 1: Adverse Reactions with ≥1% Incidence that Were Reported More Frequently with RYALTRIS than Placebo in the Safety Population in Adult and Pediatric Patients 12 Years of Age and Older with Seasonal Allergic Rhinitis RYALTRIS N=789 n (%) Olopatadine HCl Nasal Spray * N=751 n (%) Mometasone Furoate Nasal Spray * N=746 n (%) Placebo N=776 n (%) Dysgeusia 24 (3.0) 16 (2.1) 0 (0) 2 (0.3) Epistaxis 8 (1.0) 11 (1.5) 6 (0.8) 5 (0.6) Nasal discomfort 8 (1.0) 4 (0.5) 4 (0.5) 6 (0.8) * Non-US approved drugs

8.1 Pregnancy Risk Summary There are no available data on RYALTRIS or mometasone furoate use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Postmarketing experience with antihistamines, with similar mechanism of action to olopatadine, 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. Animal reproduction studies have not been conducted with RYALTRIS. However, animal reproduction studies are available for olopatadine hydrochloride and mometasone furoate. Oral administration of olopatadine hydrochloride to pregnant rats and rabbits caused a decrease in the number of live fetuses at maternal doses approximately 120 and 1600 times the maximum recommended human daily intranasal dose (MRHDID) on a mg/m 2 basis, respectively (see Data) . In animal reproduction studies with pregnant mice, rats, or rabbits, mometasone furoate caused increased fetal malformations and decreased fetal survival and growth following administration of doses that produced exposures approximately 1 to 16 times the MRHDID on a mcg/m 2 or AUC basis (see Data) . However, experience with oral corticosteroids suggests that rodents are more prone to teratogenic effects from corticosteroid exposure than humans. 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 estimated background risk of major birth defects and miscarriages in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data No reproductive toxicology studies were conducted with RYALTRIS; however, studies are available for olopatadine hydrochloride and mometasone furoate, as described below. Olopatadine hydrochloride 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 1200 times the MRHDID on a mg/m 2 basis). Olopatadine produced cleft palate at 60 mg/kg/day (approximately 120 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 1200 times the MRHDID on a mg/m 2 basis). 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 (approximately 1600 times the MRHDID on a mg/m 2 basis). In peri-/post-natal 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 120 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. Mometasone furoate In an embryo-fetal development study with pregnant mice dosed throughout the period of organogenesis, mometasone furoate produced cleft palate at a dose approximately equivalent to the MRHDID (on a mcg/m 2 basis with maternal subcutaneous doses of 60 mcg/kg and above) and decreased fetal survival at approximately 4 times the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 180 mcg/kg). No toxicity was observed with a dose that produced an exposure approximately one-half of the MRHDID (on a mcg/m 2 basis with maternal topical dermal doses of 20 mcg/kg and above). In an embryo-fetal development study with pregnant rats dosed throughout the period of organogenesis, mometasone furoate produced fetal umbilical hernia at exposures approximately 20 times the MRHDID (on a mcg/m 2 basis with maternal topical dermal doses of 600 mcg/kg and above) and delays in fetal ossification at a dose approximately 12 times the MRHDID (on a mcg/m 2 basis with maternal topical dermal doses of 300 mcg/kg and above). In another reproductive toxicity study, pregnant rats were dosed with mometasone furoate throughout pregnancy or late in gestation. Treated animals had prolonged and difficult labor, fewer live births, lower birth weight, and reduced early pup survival at a dose that was approximately equivalent to the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 15 mcg/kg). There were no findings at a dose approximately equivalent to or less than the MRHDID (on a mcg/m 2 basis with a maternal subcutaneous dose of 7.5 mcg/kg). Embryo-fetal development studies were conducted with pregnant rabbits dosed with mometasone furoate by either the topical dermal route or oral route throughout the period of organogenesis. In the study using the topical dermal route, mometasone furoate caused multiple malformations in fetuses (e.g., flexed front paws, gallbladder agenesis, umbilical hernia, hydrocephaly) at doses approximately 12 times the MRHDID (on a mcg/m 2 basis with maternal topical dermal doses of 150 mcg/kg and above). In the study using the oral route, mometasone furoate caused increased fetal resorptions and cleft palate and/or head malformations (hydrocephaly and domed head) at a dose approximately 60 times the MRHDID (on a mcg/m 2 basis with a maternal oral dose of 700 mcg/kg). At approximately 220 times the MRHDID (on a mcg/m 2 basis with a maternal oral dose of 2800 mcg/kg), most litters were aborted or resorbed. No effects were observed at a dose approximately 12 times the MRHDID (on a mcg/m 2 basis with a maternal oral dose of 140 mcg/kg).