Ryaltris Drug Information

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.

• 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 )

• 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 Hikma Specialty USA Inc. at 1-800-962-8364 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

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 .

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 .

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).

Pediatric Use The safety and effectiveness of RYALTRIS for the treatment of symptoms associated with seasonal allergic rhinitis have been established in pediatric patients 12 years and older. Use of RYALTRIS for this indication is supported by evidence from adequate and well-controlled studies in adult and pediatric patients 12 years and older . The safety and effectiveness of RYALTRIS in pediatric patients below the age of 12 years have not been established. Effect on Growth Controlled clinical studies have shown that nasal corticosteroids may cause a reduction in growth velocity in pediatric patients.

This effect has been observed in the absence of laboratory evidence of HPA axis suppression, suggesting that growth velocity is a more sensitive indicator of systemic corticosteroid exposure in pediatric patients than some commonly used tests of HPA axis function. The long-term effects of this reduction in growth velocity associated with nasal corticosteroids, including the impact on final adult height, are unknown. The potential for “catch up” growth following discontinuation of treatment with nasal corticosteroids has not been adequately studied.

The growth of pediatric patients receiving nasal corticosteroids, including RYALTRIS, should be monitored routinely (e.g., via stadiometry). The potential growth effects of prolonged treatment should be weighed against clinical benefits obtained and the risk/benefits of non-corticosteroid treatment alternatives. The potential of mometasone furoate nasal spray 50 mcg to cause growth suppression in susceptible patients or when given at higher doses cannot be ruled out.

is contraindicated in patients with known hypersensitivity to any ingredients of RYALTRIS. Hypersensitivity reactions, including wheezing, has occurred after nasal administration of mometasone furoate. Patients with known hypersensitivity to any ingredients of RYALTRIS, including mometasone furoate.

contains both olopatadine hydrochloride and mometasone furoate; therefore, the risks associated with overdosage for the individual components described below apply to RYALTRIS. Olopatadine Hydrochloride: Symptoms of antihistamine overdose may include drowsiness in adults and children. Agitation and restlessness, followed by drowsiness in children. Should overdose occur, symptomatic or supportive treatment is recommended.

Mometasone Furoate: Chronic overdosage with any corticosteroid may result in signs or symptoms of hypercorticism .