RYALTRIS Olopatadine / Mometasone Furoate 665mcg / 25mcg per actuation Nasal Spray 240actuations
RXDRUG-DR-XY47322-240
Discreet Packaging
FDA-registered Products
FDA-licensed Pharmacies
Indications/Uses
OLOPATADINE AND MOMETASONE (RYALTRIS) nasal spray is indicated for: The symptomatic treatment of seasonal or perennial allergic rhinitis and associated ocular symptoms in adults and children of 6 years and older.
Dosage/Direction for Use
Dosing Considerations: A relief of nasal allergic symptoms is observed within 10 minutes after administration of OLOPATADINE AND MOMETASONE (RYALTRIS). However, since the full effect of OLOPATADINE AND MOMETASONE (RYALTRIS) depends on its regular use, patients must be instructed to take the nasal inhalation at regular intervals.
Recommended Dose and Dosage Adjustment: Adults and Adolescents (12 Years of Age and Older): The recommended dose of OLOPATADINE AND MOMETASONE (RYALTRIS) is two sprays in each nostril twice daily (morning and evening).
Children (6 to 11 Years of Age): The recommended dose of OLOPATADINE AND MOMETASONE (RYALTRIS) is one spray per nostril twice daily (morning and evening).
Administration: Administer OLOPATADINE AND MOMETASONE (RYALTRIS) by the intranasal route only. Avoid spraying OLOPATADINE AND MOMETASONE (RYALTRIS) into the eyes or mouth.
Shake the bottle well before each use.
Priming: Prime OLOPATADINE AND MOMETASONE (RYALTRIS) before initial use by releasing 6 sprays. When OLOPATADINE AND MOMETASONE (RYALTRIS) has not been used for 14 days or more, re-prime by releasing 2 sprays or until a fine mist appears.
Missed Dose: If a single dose is missed, the next dose should be taken when it is due. A double dose should not be taken at the same time.
Recommended Dose and Dosage Adjustment: Adults and Adolescents (12 Years of Age and Older): The recommended dose of OLOPATADINE AND MOMETASONE (RYALTRIS) is two sprays in each nostril twice daily (morning and evening).
Children (6 to 11 Years of Age): The recommended dose of OLOPATADINE AND MOMETASONE (RYALTRIS) is one spray per nostril twice daily (morning and evening).
Administration: Administer OLOPATADINE AND MOMETASONE (RYALTRIS) by the intranasal route only. Avoid spraying OLOPATADINE AND MOMETASONE (RYALTRIS) into the eyes or mouth.
Shake the bottle well before each use.
Priming: Prime OLOPATADINE AND MOMETASONE (RYALTRIS) before initial use by releasing 6 sprays. When OLOPATADINE AND MOMETASONE (RYALTRIS) has not been used for 14 days or more, re-prime by releasing 2 sprays or until a fine mist appears.
Missed Dose: If a single dose is missed, the next dose should be taken when it is due. A double dose should not be taken at the same time.
Overdosage
OLOPATADINE AND MOMETASONE (RYALTRIS) contains both olopatadine hydrochloride and mometasone furoate monohydrate; therefore, the risks associated with overdosage for the individual components described as follows apply to OLOPATADINE AND MOMETASONE (RYALTRIS).
Olopatadine Hydrochloride: Symptoms of antihistamine overdose may include drowsiness in adults and, initially, agitation and restlessness, followed by drowsiness in children. There is no known specific antidote to OLOPATADINE AND MOMETASONE (RYALTRIS). Should overdose occur, symptomatic or supportive treatment is recommended, taking into account any concomitantly ingested medications.
Mometasone Furoate: Monohydrate: Because the systemic bioavailability is <1% (using a sensitive assay with a lower quantitation limit of 0.25 pg/mL) after administration of mometasone furoate via OLOPATADINE AND MOMETASONE (RYALTRIS), overdose is unlikely to require any therapy other than observation, followed by initiation of the appropriate prescribed dosage.
Olopatadine Hydrochloride: Symptoms of antihistamine overdose may include drowsiness in adults and, initially, agitation and restlessness, followed by drowsiness in children. There is no known specific antidote to OLOPATADINE AND MOMETASONE (RYALTRIS). Should overdose occur, symptomatic or supportive treatment is recommended, taking into account any concomitantly ingested medications.
Mometasone Furoate: Monohydrate: Because the systemic bioavailability is <1% (using a sensitive assay with a lower quantitation limit of 0.25 pg/mL) after administration of mometasone furoate via OLOPATADINE AND MOMETASONE (RYALTRIS), overdose is unlikely to require any therapy other than observation, followed by initiation of the appropriate prescribed dosage.
Contraindications
OLOPATADINE AND MOMETASONE (RYALTRIS) is contraindicated for patients who: Are hypersensitive to this medicine or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, Description.
Have untreated fungal, bacterial, or tuberculosis infections of the respiratory tract.
Have untreated fungal, bacterial, or tuberculosis infections of the respiratory tract.
Special Precautions
General: During transfer from systemic corticosteroid to OLOPATADINE AND MOMETASONE (RYALTRIS), some patients may experience symptoms of withdrawal from systemically active corticosteroids (e.g., joint and/or muscular pain, lassitude, and depression initially) despite relief from nasal symptoms and will require encouragement to continue OLOPATADINE AND MOMETASONE (RYALTRIS) therapy. Such transfer may also unmask pre-existing allergic conditions such as allergic conjunctivitis and eczema, previously suppressed by systemic corticosteroid therapy.
Ear/Nose/Throat: In clinical trials of 2 to 52 weeks' duration, epistaxis was observed more frequently in patients treated with OLOPATADINE AND MOMETASONE (RYALTRIS) than those who received placebo (see Adverse Reactions).
OLOPATADINE AND MOMETASONE (RYALTRIS) should not be used in the presence of untreated localized infection involving the nasal mucosa.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal surgery or trauma should not use a nasal corticosteroid until healing has occurred.
Instances of nasal ulceration and nasal septal perforation have been reported in patients following the intranasal application of antihistamines. Following the use of intranasal aerosolized corticosteroids, instances of nasal septum perforation have been reported very rarely.
As with any long-term treatment, patients using OLOPATADINE AND MOMETASONE (RYALTRIS) over several months or longer should be examined periodically for possible changes in the nasal mucosa. If localized fungal infection of the nose or pharynx develops, discontinuance of OLOPATADINE AND MOMETASONE (RYALTRIS) therapy or appropriate treatment may be required. Persistence of nasopharyngeal irritation may be an indication for discontinuing OLOPATADINE AND MOMETASONE (RYALTRIS).
Endocrine and Metabolism: Patients who are transferred from long-term administration of systemically active corticosteroids to OLOPATADINE AND MOMETASONE (RYALTRIS) require careful attention. Systemic corticosteroid withdrawal in such patients may result in adrenal insufficiency for a number of months until recovery of hypothalamic-pituitary-adrenal (HPA) axis function. If these patients exhibit signs and symptoms of adrenal insufficiency, systemic corticosteroid administration should be resumed and other modes of therapy and appropriate measures instituted.
Immune: Patients receiving corticosteroids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs.
Ophthalmologic: Following the use of intranasal aerosolized corticosteroids, instances of increased intraocular pressure have been reported very rarely.
Visual disturbance may be reported with systemic and topical (including, intranasal, inhaled and intraocular) corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes of visual disturbances; this may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Sexual Health: Fertility: Studies have not been performed to evaluate the effect of intranasal administration of OLOPATADINE AND MOMETASONE (RYALTRIS) or the respective monotherapies olopatadine hydrochloride and mometasone furoate on human fertility.
Olopatadine administered to male and female rats at oral doses of approximately 810-fold the maximum recommended human daily intranasal dose (MRHDID) (on mg/m2 basis, assuming a human body weight of 60 kg) resulted in a decrease in the fertility index and reduced implantation rate. No effects on fertility were observed at doses of approximately 100-fold the MRHDID on mg/m2 basis.
Mometasone furoate administered subcutaneously to rats at doses of approximately 5- and 1-fold the MRHDID on body weight and mg/m2 basis, respectively did not result in impairment of fertility.
Driving and Operating Machinery: Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery.
Use in Children: Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Routinely monitor the growth of pediatric patients receiving OLOPATADINE AND MOMETASONE (RYALTRIS). The safety and efficacy of OLOPATADINE AND MOMETASONE (RYALTRIS) in children under 6 years of age have not been established. No data are available.
Ear/Nose/Throat: In clinical trials of 2 to 52 weeks' duration, epistaxis was observed more frequently in patients treated with OLOPATADINE AND MOMETASONE (RYALTRIS) than those who received placebo (see Adverse Reactions).
OLOPATADINE AND MOMETASONE (RYALTRIS) should not be used in the presence of untreated localized infection involving the nasal mucosa.
Because of the inhibitory effect of corticosteroids on wound healing, patients who have experienced recent nasal surgery or trauma should not use a nasal corticosteroid until healing has occurred.
Instances of nasal ulceration and nasal septal perforation have been reported in patients following the intranasal application of antihistamines. Following the use of intranasal aerosolized corticosteroids, instances of nasal septum perforation have been reported very rarely.
As with any long-term treatment, patients using OLOPATADINE AND MOMETASONE (RYALTRIS) over several months or longer should be examined periodically for possible changes in the nasal mucosa. If localized fungal infection of the nose or pharynx develops, discontinuance of OLOPATADINE AND MOMETASONE (RYALTRIS) therapy or appropriate treatment may be required. Persistence of nasopharyngeal irritation may be an indication for discontinuing OLOPATADINE AND MOMETASONE (RYALTRIS).
Endocrine and Metabolism: Patients who are transferred from long-term administration of systemically active corticosteroids to OLOPATADINE AND MOMETASONE (RYALTRIS) require careful attention. Systemic corticosteroid withdrawal in such patients may result in adrenal insufficiency for a number of months until recovery of hypothalamic-pituitary-adrenal (HPA) axis function. If these patients exhibit signs and symptoms of adrenal insufficiency, systemic corticosteroid administration should be resumed and other modes of therapy and appropriate measures instituted.
Immune: Patients receiving corticosteroids who are potentially immunosuppressed should be warned of the risk of exposure to certain infections (e.g., chickenpox, measles) and of the importance of obtaining medical advice if such exposure occurs.
Ophthalmologic: Following the use of intranasal aerosolized corticosteroids, instances of increased intraocular pressure have been reported very rarely.
Visual disturbance may be reported with systemic and topical (including, intranasal, inhaled and intraocular) corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes of visual disturbances; this may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.
Sexual Health: Fertility: Studies have not been performed to evaluate the effect of intranasal administration of OLOPATADINE AND MOMETASONE (RYALTRIS) or the respective monotherapies olopatadine hydrochloride and mometasone furoate on human fertility.
Olopatadine administered to male and female rats at oral doses of approximately 810-fold the maximum recommended human daily intranasal dose (MRHDID) (on mg/m2 basis, assuming a human body weight of 60 kg) resulted in a decrease in the fertility index and reduced implantation rate. No effects on fertility were observed at doses of approximately 100-fold the MRHDID on mg/m2 basis.
Mometasone furoate administered subcutaneously to rats at doses of approximately 5- and 1-fold the MRHDID on body weight and mg/m2 basis, respectively did not result in impairment of fertility.
Driving and Operating Machinery: Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery.
Use in Children: Intranasal corticosteroids may cause a reduction in growth velocity when administered to pediatric patients. Routinely monitor the growth of pediatric patients receiving OLOPATADINE AND MOMETASONE (RYALTRIS). The safety and efficacy of OLOPATADINE AND MOMETASONE (RYALTRIS) in children under 6 years of age have not been established. No data are available.
Use In Pregnancy & Lactation
Pregnant Women: No adequate and well-controlled studies in pregnant women have been conducted with OLOPATADINE AND MOMETASONE (RYALTRIS) or the respective monotherapies for olopatadine hydrochloride and mometasone furoate.
Olopatadine was not teratogenic in rabbits and rats at oral doses of approximately 1600- and 1200-fold the MRHDID on mg/m2 basis, respectively. However, rats treated at approximately 120-fold or more and rabbits treated at approximately 100-fold or more the MRHDID on mg/m2 basis during the organogenesis showed a decrease in live fetuses (see Pharmacology: Toxicology under Actions)
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal), and/or subcutaneous routes (see Pharmacology: Toxicology under Actions). As with other nasal corticosteroid preparations, mometasone furoate should be used in pregnant women, nursing mothers or women of childbearing age only if the potential benefit justifies the potential risk to the mother, fetus, or infant. Infants born of mothers who received corticosteroids during pregnancy should be observed carefully for hypoadrenalism.
Because animal studies are not always predictive of human responses, OLOPATADINE AND MOMETASONE (RYALTRIS) should be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the embryo or fetus.
Breast-feeding: Olopatadine has been identified in the milk of nursing rats following oral administration.
Glucocorticosteroids are excreted in human milk.
It is unknown whether nasally administered olopatadine hydrochloride/metabolites or mometasone furoate monohydrate/metabolites are excreted in human breast milk. OLOPATADINE AND MOMETASONE (RYALTRIS) should be used by nursing mothers only if the potential benefit to the patient outweighs the potential risks to the infant.
Olopatadine was not teratogenic in rabbits and rats at oral doses of approximately 1600- and 1200-fold the MRHDID on mg/m2 basis, respectively. However, rats treated at approximately 120-fold or more and rabbits treated at approximately 100-fold or more the MRHDID on mg/m2 basis during the organogenesis showed a decrease in live fetuses (see Pharmacology: Toxicology under Actions)
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal), and/or subcutaneous routes (see Pharmacology: Toxicology under Actions). As with other nasal corticosteroid preparations, mometasone furoate should be used in pregnant women, nursing mothers or women of childbearing age only if the potential benefit justifies the potential risk to the mother, fetus, or infant. Infants born of mothers who received corticosteroids during pregnancy should be observed carefully for hypoadrenalism.
Because animal studies are not always predictive of human responses, OLOPATADINE AND MOMETASONE (RYALTRIS) should be used in pregnant women only if the potential benefit to the mother justifies the potential risk to the embryo or fetus.
Breast-feeding: Olopatadine has been identified in the milk of nursing rats following oral administration.
Glucocorticosteroids are excreted in human milk.
It is unknown whether nasally administered olopatadine hydrochloride/metabolites or mometasone furoate monohydrate/metabolites are excreted in human breast milk. OLOPATADINE AND MOMETASONE (RYALTRIS) should be used by nursing mothers only if the potential benefit to the patient outweighs the potential risks to the infant.
Adverse Reactions
Adverse Reaction Overview: The most common adverse reactions observed in clinical trials with OLOPATADINE AND MOMETASONE (RYALTRIS) were dysgeusia, headache, epistaxis, and nasal discomfort. No new clinically significant findings were observed as compared with either olopatadine hydrochloride or mometasone furoate alone. The safety profile of OLOPATADINE AND MOMETASONE (RYALTRIS) is typical of that observed with intranasal drugs of the same classes.
Tabulated list of adverse reactions: The following adverse reactions have been reported during clinical studies and post-marketing data and are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000) or not known (cannot be estimated from the available data). (See Table 1.)
Tabulated list of adverse reactions: The following adverse reactions have been reported during clinical studies and post-marketing data and are classified according to the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000) or not known (cannot be estimated from the available data). (See Table 1.)
Systemic effects of some nasal corticosteroids may occur, particularly when administered at high doses for prolonged periods.
Growth retardation has been reported in children receiving nasal corticosteroids. Growth retardation may be possible in adolescents, too.
Paediatric population: In the paediatric population (children 6 to 11 years of age), at doses half of those in adult populations, the incidence of recorded adverse events in a clinical study in seasonal allergic rhinitis, e.g., dysgeusia (1.3%), headache (1.3%), epistaxis (0.9%) and nasal discomfort (0.9%) was comparable to placebo.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Growth retardation has been reported in children receiving nasal corticosteroids. Growth retardation may be possible in adolescents, too.
Paediatric population: In the paediatric population (children 6 to 11 years of age), at doses half of those in adult populations, the incidence of recorded adverse events in a clinical study in seasonal allergic rhinitis, e.g., dysgeusia (1.3%), headache (1.3%), epistaxis (0.9%) and nasal discomfort (0.9%) was comparable to placebo.
Reporting of suspected adverse reactions: Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system.
Drug Interactions
Overview: No formal drug-drug interaction studies have been performed with OLOPATADINE AND MOMETASONE (RYALTRIS). Any drug-drug interactions from the combination of olopatadine and mometasone furoate are expected to reflect those of the individual components.
Olopatadine: In vitro studies have shown that olopatadine does not inhibit metabolic reactions which involve cytochrome P-450 isoenzymes (1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). Olopatadine is moderately bound to plasma proteins (approximately 55%). These results indicate that olopatadine is unlikely to result in interactions with other concomitantly administered medications.
Mometasone Furoate: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites with no major metabolites detected in plasma. Mometasone furoate is metabolized by CYP3A4.
Co-treatment with CYP3A inhibitors is expected to increase the risk of systemic corticosteroid side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
Concurrent use of OLOPATADINE AND MOMETASONE (RYALTRIS) 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.
Drug-Drug Interactions: The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated). (See Table 2.)
Olopatadine: In vitro studies have shown that olopatadine does not inhibit metabolic reactions which involve cytochrome P-450 isoenzymes (1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4). Olopatadine is moderately bound to plasma proteins (approximately 55%). These results indicate that olopatadine is unlikely to result in interactions with other concomitantly administered medications.
Mometasone Furoate: Studies have shown that mometasone furoate is primarily and extensively metabolized in the liver of all species investigated and undergoes extensive metabolism to multiple metabolites with no major metabolites detected in plasma. Mometasone furoate is metabolized by CYP3A4.
Co-treatment with CYP3A inhibitors is expected to increase the risk of systemic corticosteroid side-effects. The combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid side-effects, in which case patients should be monitored for systemic corticosteroid side-effects.
Concurrent use of OLOPATADINE AND MOMETASONE (RYALTRIS) 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.
Drug-Drug Interactions: The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated). (See Table 2.)
Drug-Food Interactions: Interactions with food have not been established.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions: Interactions with laboratory tests have not been established.
Drug-Herb Interactions: Interactions with herbal products have not been established.
Drug-Laboratory Test Interactions: Interactions with laboratory tests have not been established.
Caution For Usage
Incompatibilities: Not applicable.
Special Precautions for Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Special Precautions for Disposal: Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Storage
Shelf Life: 24 months.
Store at temperatures not exceeding 30°C. Do not freeze or refrigerate.
Store upright with the dust cap
Store at temperatures not exceeding 30°C. Do not freeze or refrigerate.
Store upright with the dust cap
Action
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use. ATC code: R01AD59.
Pharmacology: Mechanism of Action: OLOPATADINE AND MOMETASONE (RYALTRIS) contains both olopatadine hydrochloride and mometasone furoate; therefore, the mechanisms of action described as follows for the individual components would apply to OLOPATADINE AND MOMETASONE (RYALTRIS). These drugs represent 2 different classes of medications (histamine H1-receptor antagonist and synthetic corticosteroid).
Olopatadine Hydrochloride: Olopatadine is a histamine H1-receptor antagonist. The antihistaminic activity of olopatadine has been documented in isolated tissues, animal models, and humans.
Mometasone Furoate: Mometasone furoate is a glucocorticosteroid with local anti-inflammatory properties at doses that are minimally systemically active.
Pharmacodynamics: Olopatadine Hydrochloride: Cardiac effects: In a placebo-controlled cardiovascular safety study, 32 healthy volunteer 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 for Fridericia's correction method for heart rate) change from baseline was -2.7 msec and -3.8 msec for olopatadine, and placebo, respectively. In this study, 8 subjects treated with olopatadine had a QTcF change from baseline of 30-60 msec, 1 subject had a QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. Eight subjects treated with placebo had a QTcF change from baseline 30-60 msec, no subjects had a QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. In a 12-month study in 429 perennial allergic rhinitis patients treated with olopatadine hydrochloride nasal spray, 665 mcg per spray, 2 sprays per nostril twice daily, no evidence of any effect of olopatadine hydrochloride on QT prolongation was observed.
Mometasone Furoate Monohydrate: In two clinical studies utilizing nasal antigen challenge, mometasone furoate monohydrate aqueous nasal spray has shown anti-inflammatory activity in both the early- and late-phase allergic responses. This has been demonstrated by decreases (vs. placebo) in histamine and eosinophil activity and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known.
Pharmacokinetics: Absorption: After repeated intranasal administration of 2 sprays per nostril of OLOPATADINE AND MOMETASONE (RYALTRIS) (2660 mcg of olopatadine hydrochloride and 100 mcg of mometasone furoate) twice daily in patients with seasonal allergic rhinitis, the mean (± standard deviation) peak plasma exposure (Cmax) was 19.80 ± 7.01 ng/mL for olopatadine and 9.92 ± 3.74 pg/mL for mometasone furoate, and the mean exposure over the dosing regimen (AUCtau) was 88.77 ± 23.87 ng/mL*hr for olopatadine and 58.40 ± 27.00 pg/mL*hr for mometasone furoate. The median time to peak exposure from a single dose was 1 hour for both olopatadine and mometasone furoate.
The systemic bioavailability of olopatadine and mometasone furoate from OLOPATADINE AND MOMETASONE (RYALTRIS) following intranasal administration was estimated to be comparable with olopatadine hydrochloride and mometasone furoate nasal sprays administered as monotherapies.
Distribution: The 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 binds predominately to human serum albumin. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.
Metabolism: Olopatadine is not extensively metabolized. Based on plasma metabolite profiles following oral administration of [14C] olopatadine, at least 6 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 CYP isoenzymes 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 33900 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.
Studies have shown that any portion of a mometasone furoate dose that is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6β-hydroxy-mometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by CYP3A4.
Elimination: Following single-dose intranasal administration of a combination of olopatadine and mometasone furoate (2660 µg of olopatadine HCl and 200 µg of mometasone furoate), the mean elimination half-lives of olopatadine and mometasone furoate were 8.63 and 18.11 hours, respectively.
Olopatadine is mainly eliminated through urinary excretion. Approximately 70% of a [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.
Any absorbed mometasone furoate is excreted as metabolites mostly via the bile, and to limited extent, into the urine.
Special Populations and Conditions: Pediatrics: OLOPATADINE AND MOMETASONE (RYALTRIS) pharmacokinetics has not been investigated in patients under 12 years of age (see Precautions).
Geriatrics: Based on population pharmacokinetic analysis among patients 12 years of age and older, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by age.
Sex: Based on population pharmacokinetic analysis, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by gender.
Ethnic Origin: Based on population pharmacokinetic analysis, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by race.
Hepatic Insufficiency: No specific pharmacokinetic study examining the effect of hepatic impairment was conducted with OLOPATADINE AND MOMETASONE (RYALTRIS). Metabolism of olopatadine is a minor route of elimination.
Administration of a single inhaled dose of 400 mcg mometasone furoate to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/mL). The observed peak plasma concentrations appeared to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.
Based on data from the individual components, no adjustment of the dosing regimen of OLOPATADINE AND MOMETASONE (RYALTRIS) is warranted in patients with hepatic impairment.
Renal Insufficiency: The mean Cmax values for olopatadine following single intranasal doses were not markedly different between healthy subjects (18.1 ng/mL) and patients with mild, moderate, and severe renal impairment (ranging from 15.5 to 21.6 ng/mL). 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 were approximately 10-fold lower than those observed after higher, 20 mg oral doses, twice daily, which were well tolerated.
The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated. Based on data from the individual components, no adjustment of the dosing regimen of RYALTRIS is warranted in patients with renal impairment.
Toxicology: Non-Clinical Toxicology: Acute Toxicity: Olopatadine Hydrochloride: The acute toxicity of olopatadine hydrochloride has been investigated in mice, rats and dogs. Mice and rats demonstrated that olopatadine hydrochloride was not an acute toxicity hazard with oral LD50 values greater than 1150 mg/kg and 3870 mg/kg for mice and rats, respectively.
Mometasone Furoate Monohydrate: Two acute inhalation toxicity studies were conducted in mice (i.e., 4-hr whole-body exposure to micronized, pure, mometasone furoate powder). In the first study, the mean estimated doses were 582 mg/kg (in mice) and 394 mg/kg (for rats), assuming 100% deposition. No clinical signs were observed in either species during the 36-day post-exposure observation period. However, lower body weights compared to pre-treatment values were observed in both species. In the second study, rats were exposed by whole body exposure to 0.68 mg/L micronized mometasone furoate powder for 4 hours, and then observed for 3 weeks. Weight loss occurred during the observation period; while rales, ano-genital staining, soft stools and emaciation were the principal clinical observations. At necropsy, several rats had discoloured lungs, small spleens and discoloured brown skin.
Multiple-Dose Toxicity: Olopatadine Hydrochloride and Mometasone Furoate Monohydrate: No test article-related mortality or adverse systemic effects were observed in rats treated intranasally with OLOPATADINE AND MOMETASONE (RYALTRIS) for 13 weeks and no target organs were identified. No evidence of local toxicity was noted. No notable differences were observed between OLOPATADINE AND MOMETASONE (RYALTRIS) and their monotherapy comparators or the placebo. At the no-observed-adverse-effect level (NOAEL) dose (1.064/0.04 mg/day olopatadine HCl/mometasone furoate) in the 13-week rat toxicity study, there is a 2.3- and 8-fold multiple of the MRHDID of monocomponents of OLOPATADINE AND MOMETASONE (RYALTRIS) (5.320 mg olopatadine HCl [4.8 mg olopatadine base] and 0.2 mg mometasone furoate), based on nasal surface area and body surface area, respectively. Based on body weight dose normalization, there is a 48-fold multiple of the MRHDID of 0.089 mg/kg (5.320 mg/day) olopatadine HCl and 0.0033 mg/kg (0.20 mg/day) mometasone furoate, assuming 60 kg body weight. The NOAEL dose of the comparator monocomponent in the study was 1.064 mg/day and 0.04 mg/day for olopatadine HCl and mometasone furoate, respectively.
Olopatadine Hydrochloride: Sub-chronic and chronic oral toxicity studies in rats and dogs demonstrated that the liver and kidney were target organs for olopatadine hydrochloride toxicity. In rats, ophthalmology and hematology parameters were unaffected following chronic administration of olopatadine hydrochloride. In chronic dog studies, ophthalmology, hematology, blood chemistry and organ weight parameters were unaffected by olopatadine hydrochloride administration. The no toxic effect doses were 6 and 5 mg/kg/day in 13- and 52-week repeat dose oral toxicity study in rat and dogs, respectively.
Mometasone Furoate Monohydrate: The intranasal irritation potential of mometasone furoate aqueous nasal suspensions were assessed in beagle dogs administered daily doses of up to 4.0 mg/ dog for three days, one week or one month. The aqueous nasal suspensions did not induce irritation in the nasal mucosa, and no compound-related changes were observed after one month of administration.
Mometasone furoate aqueous nasal suspension was well tolerated in toxicity studies conducted in rats and dogs for 6 months. Rats received doses of up to 0.600 mg/kg or 0.18 mg/day (approximately 182- and 30-fold the MRHDID of 0.2 mg/day mometasone furoate delivered by OLOPATADINE AND MOMETASONE (RYALTRIS) on body weight and mg/m2 basis, respectively; dogs received doses of up to 0.15 mg/kg or 2.0 mg/day (approximately 45- and 24-fold the MRHDID on body weight and mg/m2 basis, respectively). Rats treated with 0.6 mg/kg experienced hair loss on the back during the last 5 weeks, which correlated with hypotrichosis. The no-effect dose for pharmacologic effects in rats was 0.050 mg/kg (approximately 15- and 2-fold the MRHDID on body weight and mg/m2 basis, respectively) based on low body weight gains at higher doses. Dogs treated with 0.15 mg/kg demonstrated eosinophil counts, which were lower than pre-test and concurrent controls after 4, 13 and 26 weeks. In addition, adrenocorticotropic hormone (ACTH) response in the 0.045 and 0.15 mg/kg dose groups was lower than control. These differences were dose-related and were attributed to mometasone furoate. No evidence of nasal irritation was present at any dose in either the rat or the dog study. No target organs of systemic toxicity were identified in either study.
Mometasone furoate aqueous nasal spray was well tolerated when administered intranasally to dogs for one year at doses of up to 2.0 mg/day. In the 2.0 mg/ day dose group, an increased incidence of alopecia, minimal decreases in lymphocytes and eosinophils, decreases in basal and post-ACTH cortisol response, lower adrenal gland weights, small or atrophied adrenal glands, epidermal atrophy, minimal splenic lymphoid atrophy, minimal focal epithelial attenuation in the nasal turbinates and retained luminal mucus were observed. Dogs treated with ≥0.2 mg/day demonstrated a dose-related increase in smaller or absent lymphoid aggregates. With the exception of minimally increased retained luminal mucus in the 2.0 mg/day dose group, there was no evidence of irritation or inflammation in the nasal turbinates of mometasone furoate-treated dogs. Thus, the changes in the lymphoid aggregates were considered a localized corticosteroid response associated with application and were not considered to be of toxicologic significance.
Mutagenicity: Olopatadine Hydrochloride: Olopatadine was tested in a series of in vitro and in vivo mutagenesis studies. The results of these studies demonstrated that treatment with olopatadine did not induce genetic mutations or chromosomal aberrations.
Mometasone Furoate Monohydrate: Mometasone furoate was non-mutagenic in the mouse lymphoma assay and the salmonella/mammalian microsome mutagenicity bioassay. Mometasone furoate was negative in the mouse bone marrow erythrocyte micronucleus assay, the rat bone marrow clastogenicity assay, the UDS assay in rat hepatocytes and the mouse mitotic male germ-cell clastogenicity assay, and the Chinese hamster lung cell chromosomal aberrations assay. At cytotoxic doses in Chinese hamster ovary cell cultures, mometasone furoate induced a dose-related increase in simple chromosome aberrations when continuously exposed (7.5 hours) in the non-activation phase, but not in the presence of rat liver S9 fraction. This finding is not considered to be of significance in the risk assessment of mometasone furoate, since the S9 phase of the chromosomal-aberration assay and all in vivo assays were negative.
Carcinogenicity: Olopatadine Hydrochloride: Olopatadine demonstrated no tumorogenic potential in mice at oral doses up to 500 mg/kg/day (approximately 500-fold the MRHDID on mg/m2 basis) for 78 weeks or in rats at oral doses up to 200 mg/kg/day (approximately 500-fold the MRHDID on a mg/m2 basis) for 104 weeks.
Mometasone Furoate Monohydrate: The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 mcg/L was investigated in 24-month studies in mice and rats. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumour types. The apparent increase in mouse bladder/seminal vesicle mesenchymal tumours is considered to have no relevance in human carcinogenic risk assessment since it is a species- and strain-specific finding with no human correlate. The greater incidence of pancreatic islet cell hyperplasia in male rats who received 1.0 and 2.0 mcg/L is attributed to the well-established metabolic effects (increased glucose and/or insulin resistance) following prolonged administration of glucocorticoids. Increases in pancreatic islet cell tumours, which are induced by other steroids, reflects a non-genotoxic mechanism operative in an endocrinologically uniquely sensitively species.
Reproductive Toxicology: Olopatadine Hydrochloride: In reproductive studies in rats, impairment of fertility (i.e., decreased fertility index, reduced implantation rate) was observed at an oral dose of 400 mg/kg/day (approximately 810-fold the MRHDID on a mg/m2 basis). No effect on fertility was observed at an oral dose of 50 mg/kg/day (approximately 100-fold the MRHDID on a mg/m2 basis).
In an oral embryofetal development study, pregnant rats were dosed throughout the period of organogenesis at doses up to 600 mg/kg/day. A decrease in the number of live fetuses was observed at doses greater or equal to 60 mg/kg/day (approximately 120-fold the MRHDID on a mg/m2 basis). Olopatadine was not teratogenic at any doses up to 600 mg/kg/day (approximately 1200-fold the MRHDID on a mg/m2 basis). In an oral embryofetal 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 doses equal to or greater than 25 mg/kg/day (approximately 100-fold the MRHDID on a mg/m2 basis). Olopatadine was not teratogenic at any dose up to 400 mg/ kg/ day (approximately 1600-fold the MRHDID on a mg/m2 basis).
Further, rats treated with 600 mg/kg/day (approximately 1200-fold the MRHDID on a mg/m2 basis) of olopatadine during late gestation through the lactation period showed a decrease in neonatal survival and body weight.
Mometasone Furoate Monohydrate: In subcutaneous Segment I and III studies in rats, mometasone furoate was well tolerated at doses up to 7.5 mcg/kg (approximately 2.3- and 0.4-fold the MRHDID on body weight and mg/m2 basis, respectively). At 15 mcg/kg (approximately 5- and 1-fold the MRHDID on body weight and mg/m2 basis, respectively), prolonged gestation and prolonged and difficult labour occurred with a reduction in offspring survival and body weight gain or body weight gain. There was no effect on fertility. Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal), and/or subcutaneous routes. Umbilical hernia occurred in rats administered ≥ 600 mcg/kg dermally (approximately 182- and 30-fold the MRHDID on body weight and mg/m2 basis, respectively), cleft palate in mice administered 180 mcg/kg subcutaneously (approximately 55- and 4-fold the MRHDID on body weight and mg/m2 basis, respectively), and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits administered ≥ 150 mcg/kg dermally (approximately 45- and 15-fold the MRHDID on body weight and mg/m2 basis, respectively). In these teratogenicity studies, there were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
Pharmacology: Mechanism of Action: OLOPATADINE AND MOMETASONE (RYALTRIS) contains both olopatadine hydrochloride and mometasone furoate; therefore, the mechanisms of action described as follows for the individual components would apply to OLOPATADINE AND MOMETASONE (RYALTRIS). These drugs represent 2 different classes of medications (histamine H1-receptor antagonist and synthetic corticosteroid).
Olopatadine Hydrochloride: Olopatadine is a histamine H1-receptor antagonist. The antihistaminic activity of olopatadine has been documented in isolated tissues, animal models, and humans.
Mometasone Furoate: Mometasone furoate is a glucocorticosteroid with local anti-inflammatory properties at doses that are minimally systemically active.
Pharmacodynamics: Olopatadine Hydrochloride: Cardiac effects: In a placebo-controlled cardiovascular safety study, 32 healthy volunteer 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 for Fridericia's correction method for heart rate) change from baseline was -2.7 msec and -3.8 msec for olopatadine, and placebo, respectively. In this study, 8 subjects treated with olopatadine had a QTcF change from baseline of 30-60 msec, 1 subject had a QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. Eight subjects treated with placebo had a QTcF change from baseline 30-60 msec, no subjects had a QTcF change from baseline greater than 60 msec, and no subjects had QTcF values greater than 500 msec. In a 12-month study in 429 perennial allergic rhinitis patients treated with olopatadine hydrochloride nasal spray, 665 mcg per spray, 2 sprays per nostril twice daily, no evidence of any effect of olopatadine hydrochloride on QT prolongation was observed.
Mometasone Furoate Monohydrate: In two clinical studies utilizing nasal antigen challenge, mometasone furoate monohydrate aqueous nasal spray has shown anti-inflammatory activity in both the early- and late-phase allergic responses. This has been demonstrated by decreases (vs. placebo) in histamine and eosinophil activity and reductions (vs. baseline) in eosinophils, neutrophils, and epithelial cell adhesion proteins. The clinical significance of these findings is not known.
Pharmacokinetics: Absorption: After repeated intranasal administration of 2 sprays per nostril of OLOPATADINE AND MOMETASONE (RYALTRIS) (2660 mcg of olopatadine hydrochloride and 100 mcg of mometasone furoate) twice daily in patients with seasonal allergic rhinitis, the mean (± standard deviation) peak plasma exposure (Cmax) was 19.80 ± 7.01 ng/mL for olopatadine and 9.92 ± 3.74 pg/mL for mometasone furoate, and the mean exposure over the dosing regimen (AUCtau) was 88.77 ± 23.87 ng/mL*hr for olopatadine and 58.40 ± 27.00 pg/mL*hr for mometasone furoate. The median time to peak exposure from a single dose was 1 hour for both olopatadine and mometasone furoate.
The systemic bioavailability of olopatadine and mometasone furoate from OLOPATADINE AND MOMETASONE (RYALTRIS) following intranasal administration was estimated to be comparable with olopatadine hydrochloride and mometasone furoate nasal sprays administered as monotherapies.
Distribution: The 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 binds predominately to human serum albumin. The in vitro protein binding for mometasone furoate was reported to be 98% to 99% in concentration range of 5 to 500 ng/mL.
Metabolism: Olopatadine is not extensively metabolized. Based on plasma metabolite profiles following oral administration of [14C] olopatadine, at least 6 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 CYP isoenzymes 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 33900 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.
Studies have shown that any portion of a mometasone furoate dose that is swallowed and absorbed undergoes extensive metabolism to multiple metabolites. There are no major metabolites detectable in plasma. Upon in vitro incubation, one of the minor metabolites formed is 6β-hydroxy-mometasone furoate. In human liver microsomes, the formation of the metabolite is regulated by CYP3A4.
Elimination: Following single-dose intranasal administration of a combination of olopatadine and mometasone furoate (2660 µg of olopatadine HCl and 200 µg of mometasone furoate), the mean elimination half-lives of olopatadine and mometasone furoate were 8.63 and 18.11 hours, respectively.
Olopatadine is mainly eliminated through urinary excretion. Approximately 70% of a [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.
Any absorbed mometasone furoate is excreted as metabolites mostly via the bile, and to limited extent, into the urine.
Special Populations and Conditions: Pediatrics: OLOPATADINE AND MOMETASONE (RYALTRIS) pharmacokinetics has not been investigated in patients under 12 years of age (see Precautions).
Geriatrics: Based on population pharmacokinetic analysis among patients 12 years of age and older, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by age.
Sex: Based on population pharmacokinetic analysis, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by gender.
Ethnic Origin: Based on population pharmacokinetic analysis, the pharmacokinetics of olopatadine and mometasone furoate with OLOPATADINE AND MOMETASONE (RYALTRIS) was not influenced by race.
Hepatic Insufficiency: No specific pharmacokinetic study examining the effect of hepatic impairment was conducted with OLOPATADINE AND MOMETASONE (RYALTRIS). Metabolism of olopatadine is a minor route of elimination.
Administration of a single inhaled dose of 400 mcg mometasone furoate to subjects with mild (n=4), moderate (n=4), and severe (n=4) hepatic impairment resulted in only 1 or 2 subjects in each group having detectable peak plasma concentrations of mometasone furoate (ranging from 50 to 105 pcg/mL). The observed peak plasma concentrations appeared to increase with severity of hepatic impairment; however, the numbers of detectable levels were few.
Based on data from the individual components, no adjustment of the dosing regimen of OLOPATADINE AND MOMETASONE (RYALTRIS) is warranted in patients with hepatic impairment.
Renal Insufficiency: The mean Cmax values for olopatadine following single intranasal doses were not markedly different between healthy subjects (18.1 ng/mL) and patients with mild, moderate, and severe renal impairment (ranging from 15.5 to 21.6 ng/mL). 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 were approximately 10-fold lower than those observed after higher, 20 mg oral doses, twice daily, which were well tolerated.
The effects of renal impairment on mometasone furoate pharmacokinetics have not been adequately investigated. Based on data from the individual components, no adjustment of the dosing regimen of RYALTRIS is warranted in patients with renal impairment.
Toxicology: Non-Clinical Toxicology: Acute Toxicity: Olopatadine Hydrochloride: The acute toxicity of olopatadine hydrochloride has been investigated in mice, rats and dogs. Mice and rats demonstrated that olopatadine hydrochloride was not an acute toxicity hazard with oral LD50 values greater than 1150 mg/kg and 3870 mg/kg for mice and rats, respectively.
Mometasone Furoate Monohydrate: Two acute inhalation toxicity studies were conducted in mice (i.e., 4-hr whole-body exposure to micronized, pure, mometasone furoate powder). In the first study, the mean estimated doses were 582 mg/kg (in mice) and 394 mg/kg (for rats), assuming 100% deposition. No clinical signs were observed in either species during the 36-day post-exposure observation period. However, lower body weights compared to pre-treatment values were observed in both species. In the second study, rats were exposed by whole body exposure to 0.68 mg/L micronized mometasone furoate powder for 4 hours, and then observed for 3 weeks. Weight loss occurred during the observation period; while rales, ano-genital staining, soft stools and emaciation were the principal clinical observations. At necropsy, several rats had discoloured lungs, small spleens and discoloured brown skin.
Multiple-Dose Toxicity: Olopatadine Hydrochloride and Mometasone Furoate Monohydrate: No test article-related mortality or adverse systemic effects were observed in rats treated intranasally with OLOPATADINE AND MOMETASONE (RYALTRIS) for 13 weeks and no target organs were identified. No evidence of local toxicity was noted. No notable differences were observed between OLOPATADINE AND MOMETASONE (RYALTRIS) and their monotherapy comparators or the placebo. At the no-observed-adverse-effect level (NOAEL) dose (1.064/0.04 mg/day olopatadine HCl/mometasone furoate) in the 13-week rat toxicity study, there is a 2.3- and 8-fold multiple of the MRHDID of monocomponents of OLOPATADINE AND MOMETASONE (RYALTRIS) (5.320 mg olopatadine HCl [4.8 mg olopatadine base] and 0.2 mg mometasone furoate), based on nasal surface area and body surface area, respectively. Based on body weight dose normalization, there is a 48-fold multiple of the MRHDID of 0.089 mg/kg (5.320 mg/day) olopatadine HCl and 0.0033 mg/kg (0.20 mg/day) mometasone furoate, assuming 60 kg body weight. The NOAEL dose of the comparator monocomponent in the study was 1.064 mg/day and 0.04 mg/day for olopatadine HCl and mometasone furoate, respectively.
Olopatadine Hydrochloride: Sub-chronic and chronic oral toxicity studies in rats and dogs demonstrated that the liver and kidney were target organs for olopatadine hydrochloride toxicity. In rats, ophthalmology and hematology parameters were unaffected following chronic administration of olopatadine hydrochloride. In chronic dog studies, ophthalmology, hematology, blood chemistry and organ weight parameters were unaffected by olopatadine hydrochloride administration. The no toxic effect doses were 6 and 5 mg/kg/day in 13- and 52-week repeat dose oral toxicity study in rat and dogs, respectively.
Mometasone Furoate Monohydrate: The intranasal irritation potential of mometasone furoate aqueous nasal suspensions were assessed in beagle dogs administered daily doses of up to 4.0 mg/ dog for three days, one week or one month. The aqueous nasal suspensions did not induce irritation in the nasal mucosa, and no compound-related changes were observed after one month of administration.
Mometasone furoate aqueous nasal suspension was well tolerated in toxicity studies conducted in rats and dogs for 6 months. Rats received doses of up to 0.600 mg/kg or 0.18 mg/day (approximately 182- and 30-fold the MRHDID of 0.2 mg/day mometasone furoate delivered by OLOPATADINE AND MOMETASONE (RYALTRIS) on body weight and mg/m2 basis, respectively; dogs received doses of up to 0.15 mg/kg or 2.0 mg/day (approximately 45- and 24-fold the MRHDID on body weight and mg/m2 basis, respectively). Rats treated with 0.6 mg/kg experienced hair loss on the back during the last 5 weeks, which correlated with hypotrichosis. The no-effect dose for pharmacologic effects in rats was 0.050 mg/kg (approximately 15- and 2-fold the MRHDID on body weight and mg/m2 basis, respectively) based on low body weight gains at higher doses. Dogs treated with 0.15 mg/kg demonstrated eosinophil counts, which were lower than pre-test and concurrent controls after 4, 13 and 26 weeks. In addition, adrenocorticotropic hormone (ACTH) response in the 0.045 and 0.15 mg/kg dose groups was lower than control. These differences were dose-related and were attributed to mometasone furoate. No evidence of nasal irritation was present at any dose in either the rat or the dog study. No target organs of systemic toxicity were identified in either study.
Mometasone furoate aqueous nasal spray was well tolerated when administered intranasally to dogs for one year at doses of up to 2.0 mg/day. In the 2.0 mg/ day dose group, an increased incidence of alopecia, minimal decreases in lymphocytes and eosinophils, decreases in basal and post-ACTH cortisol response, lower adrenal gland weights, small or atrophied adrenal glands, epidermal atrophy, minimal splenic lymphoid atrophy, minimal focal epithelial attenuation in the nasal turbinates and retained luminal mucus were observed. Dogs treated with ≥0.2 mg/day demonstrated a dose-related increase in smaller or absent lymphoid aggregates. With the exception of minimally increased retained luminal mucus in the 2.0 mg/day dose group, there was no evidence of irritation or inflammation in the nasal turbinates of mometasone furoate-treated dogs. Thus, the changes in the lymphoid aggregates were considered a localized corticosteroid response associated with application and were not considered to be of toxicologic significance.
Mutagenicity: Olopatadine Hydrochloride: Olopatadine was tested in a series of in vitro and in vivo mutagenesis studies. The results of these studies demonstrated that treatment with olopatadine did not induce genetic mutations or chromosomal aberrations.
Mometasone Furoate Monohydrate: Mometasone furoate was non-mutagenic in the mouse lymphoma assay and the salmonella/mammalian microsome mutagenicity bioassay. Mometasone furoate was negative in the mouse bone marrow erythrocyte micronucleus assay, the rat bone marrow clastogenicity assay, the UDS assay in rat hepatocytes and the mouse mitotic male germ-cell clastogenicity assay, and the Chinese hamster lung cell chromosomal aberrations assay. At cytotoxic doses in Chinese hamster ovary cell cultures, mometasone furoate induced a dose-related increase in simple chromosome aberrations when continuously exposed (7.5 hours) in the non-activation phase, but not in the presence of rat liver S9 fraction. This finding is not considered to be of significance in the risk assessment of mometasone furoate, since the S9 phase of the chromosomal-aberration assay and all in vivo assays were negative.
Carcinogenicity: Olopatadine Hydrochloride: Olopatadine demonstrated no tumorogenic potential in mice at oral doses up to 500 mg/kg/day (approximately 500-fold the MRHDID on mg/m2 basis) for 78 weeks or in rats at oral doses up to 200 mg/kg/day (approximately 500-fold the MRHDID on a mg/m2 basis) for 104 weeks.
Mometasone Furoate Monohydrate: The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 mcg/L was investigated in 24-month studies in mice and rats. Typical glucocorticoid-related effects, including several non-neoplastic lesions, were observed. No statistically significant dose-response relationship was detected for any of the tumour types. The apparent increase in mouse bladder/seminal vesicle mesenchymal tumours is considered to have no relevance in human carcinogenic risk assessment since it is a species- and strain-specific finding with no human correlate. The greater incidence of pancreatic islet cell hyperplasia in male rats who received 1.0 and 2.0 mcg/L is attributed to the well-established metabolic effects (increased glucose and/or insulin resistance) following prolonged administration of glucocorticoids. Increases in pancreatic islet cell tumours, which are induced by other steroids, reflects a non-genotoxic mechanism operative in an endocrinologically uniquely sensitively species.
Reproductive Toxicology: Olopatadine Hydrochloride: In reproductive studies in rats, impairment of fertility (i.e., decreased fertility index, reduced implantation rate) was observed at an oral dose of 400 mg/kg/day (approximately 810-fold the MRHDID on a mg/m2 basis). No effect on fertility was observed at an oral dose of 50 mg/kg/day (approximately 100-fold the MRHDID on a mg/m2 basis).
In an oral embryofetal development study, pregnant rats were dosed throughout the period of organogenesis at doses up to 600 mg/kg/day. A decrease in the number of live fetuses was observed at doses greater or equal to 60 mg/kg/day (approximately 120-fold the MRHDID on a mg/m2 basis). Olopatadine was not teratogenic at any doses up to 600 mg/kg/day (approximately 1200-fold the MRHDID on a mg/m2 basis). In an oral embryofetal 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 doses equal to or greater than 25 mg/kg/day (approximately 100-fold the MRHDID on a mg/m2 basis). Olopatadine was not teratogenic at any dose up to 400 mg/ kg/ day (approximately 1600-fold the MRHDID on a mg/m2 basis).
Further, rats treated with 600 mg/kg/day (approximately 1200-fold the MRHDID on a mg/m2 basis) of olopatadine during late gestation through the lactation period showed a decrease in neonatal survival and body weight.
Mometasone Furoate Monohydrate: In subcutaneous Segment I and III studies in rats, mometasone furoate was well tolerated at doses up to 7.5 mcg/kg (approximately 2.3- and 0.4-fold the MRHDID on body weight and mg/m2 basis, respectively). At 15 mcg/kg (approximately 5- and 1-fold the MRHDID on body weight and mg/m2 basis, respectively), prolonged gestation and prolonged and difficult labour occurred with a reduction in offspring survival and body weight gain or body weight gain. There was no effect on fertility. Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Teratology studies were conducted in rats, mice and rabbits by the oral, topical (dermal), and/or subcutaneous routes. Umbilical hernia occurred in rats administered ≥ 600 mcg/kg dermally (approximately 182- and 30-fold the MRHDID on body weight and mg/m2 basis, respectively), cleft palate in mice administered 180 mcg/kg subcutaneously (approximately 55- and 4-fold the MRHDID on body weight and mg/m2 basis, respectively), and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits administered ≥ 150 mcg/kg dermally (approximately 45- and 15-fold the MRHDID on body weight and mg/m2 basis, respectively). In these teratogenicity studies, there were also reductions in maternal body weight gains, effects on fetal growth (lower fetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
MedsGo Class
Nasal Decongestants & Other Nasal Preparations
Features
Brand
Ryaltris
Full Details
Dosage Strength
665 mcg / 25 mcg per actuation
Drug Ingredients
- Mometasone
- Olopatadine
Drug Packaging
Nasal Spray 240 act.
Generic Name
Olopatadine / Mometasone Furoate
Dosage Form
Nasal Spray
Registration Number
DR-XY47322
Drug Classification
Prescription Drug (RX)
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