RYALTRIS 25 µg/600 µg/dose Nasal powder suspension Vial/30ml

Nasal spray suspension (white and homogeneous).
Bottle of 30 ml (240 sprays), with manual actuation device for the spray's metering pump.
Box of 1.

One delivered dose (the dose that comes out of the spray device) contains an amount of mometasone furoate monohydrate equivalent to 25 micrograms of mometasone furoate and an amount of olopatadine equivalent to 600 micrograms of olopatadine.

Excipient with known effect:

Each spray contains 0,02 mg of benzalkonium chloride.

Excipients:

RYALTRIS is indicated, in adults and adolescents aged 12 years and older, for the treatment of moderate to severe nasal symptoms of allergic rhinitis.

Dosage

Adults and adolescents (aged 12 years and above)

The usual recommended dose is two sprays in each nostril, twice a day (morning and evening).

Children under 12 years of age

The use of RYALTRIS is not recommended in children under 12 years of age, as safety and efficacy have not been established in this age group.

Elderly patients

No dose adjustment is necessary in this population.

Renal and hepatic impairment

Although no data are available in patients with renal or hepatic impairment, no dose adjustment should be necessary in these populations given the absorption, metabolism and elimination of the active substances (see section Pharmacokinetics).

Method of administration

RYALTRIS must be administered by the nasal route only.

Before administering the first dose, shake the bottle well and perform 6 pump actuations (until a uniform spray is obtained). If the pump has not been used for 14 days or more, it must be re-primed with 2 actuations until a uniform spray is obtained, before any further use.

Shake the bottle for at least 10 seconds before each use. After use, carefully wipe the spray nozzle with a clean cloth or paper tissue and replace the cap so as to prevent the nozzle from clogging. The bottle must be discarded when the indicated number of doses has been reached, or within 2 months of first use.

Hypersensitivity to the active substances or to any of the excipients listed in section Composition.

RYALTRIS must not be used in the presence of an untreated localised infection of the nasal mucosa, such as herpes.

Due to the inhibitory effect of corticosteroids on wound healing, patients who have recently undergone nasal surgery or nasal trauma must refrain from using a nasal corticosteroid until healing has occurred.

Local effects in the nasal passages

Cases of nasal ulceration and perforation of the nasal septum have been reported in patients following intranasal administration of antihistamines.

Cases of nasal septum perforation have been reported following intranasal administration of corticosteroids.

Patients using RYALTRIS for several months or a longer period should be regularly examined to detect any change in the nasal mucosa.

RYALTRIS is not recommended in cases of perforation of the nasal septum (see section Adverse effects).

Cases of epistaxis have been reported in some patients following intranasal administration of antihistamines and corticosteroids (see section Adverse effects).

During clinical studies involving intranasal administration of mometasone furoate, localised infections of the nose and pharynx by Candida albicans have occurred. When such an infection occurs, it may require treatment with an appropriate local therapy and discontinuation of RYALTRIS treatment. Patients using RYALTRIS for several months or longer should be examined regularly to detect any presence of infection by Candida or other signs of adverse effects on the nasal mucosa.

Visual disorders

Visual disturbances may be reported with the use of systemic and topical corticosteroids (including intranasal administration). If a patient presents with symptoms such as blurred vision or other visual disturbances, referral to an ophthalmologist should be considered to evaluate potential causes of visual disturbances, such as cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR), which have been reported after the use of systemic and topical corticosteroids.

Hypersensitivity reactions

Hypersensitivity reactions, including cases of wheezing, may occur after intranasal administration of mometasone furoate monohydrate and olopatadine hydrochloride. Discontinue administration of RYALTRIS if such reactions occur (see section Adverse effects).

Immunosuppression

Persons using immunosuppressive medicinal products, such as corticosteroids, are more susceptible to infections than healthy individuals. Chickenpox and measles, for example, may have a more severe, even fatal, course in susceptible children or adults using corticosteroids. Particular caution is required to avoid exposure in children or adults who have not had these diseases or who have not been adequately immunised against them. It is not known to what extent the dose, route of administration and duration of corticosteroid administration influence the risk of developing a generalised infection.

Corticosteroids should be used with caution, or avoided altogether, in patients with active or asymptomatic tuberculous infections of the respiratory tract, untreated localised or systemic fungal or bacterial infections, systemic viral or parasitic infections, or ocular herpes simplex, due to the risk of aggravation of these infections.

Systemic effects of corticosteroids

Potential systemic effects may include Cushing's syndrome, cushingoid features, adrenal suppression, growth retardation in children and adolescents, cataract, glaucoma and, more rarely, a range of psychological or behavioural effects, including psychomotor hyperactivity, sleep disorders, anxiety, depression or aggressiveness (particularly in children).

When intranasal corticosteroids are used at doses higher than the recommended doses or if they are used in persons sensitive to the recommended doses, systemic corticosteroid effects such as hypercorticism and adrenal suppression may occur. If such changes occur, the dose of RYALTRIS should be discontinued slowly, in accordance with accepted procedures for discontinuing oral corticosteroid therapy. Concomitant use of intranasal corticosteroids and other inhaled corticosteroids is likely to increase the risk of signs or symptoms of hypercorticism and/or suppression of the HPA axis.

If there is evidence supporting the use of doses above the recommended doses, additional systemic corticosteroid cover should be considered during periods of stress or elective surgery.

Replacing a systemic corticosteroid with a topical corticosteroid may be accompanied by signs of adrenal insufficiency, and some patients may experience withdrawal symptoms (e.g. joint and/or muscle pain, lassitude and depression). Patients previously treated long-term with systemic corticosteroids whose treatment is switched to topical corticosteroids should be closely monitored for acute adrenal insufficiency in response to stress. In patients who suffer from asthma or other clinical conditions requiring long-term systemic corticosteroid treatment, too rapid a reduction of systemic corticosteroids may result in a serious exacerbation of their symptoms.

Somnolence

Like other antihistamines, olopatadine may cause drowsiness in the same patients when absorbed systemically.

Patients should be advised to exercise caution when performing hazardous activities requiring high alertness and motor coordination, such as operating machinery or driving a vehicle, after administration of RYALTRIS. Concomitant use of RYALTRIS with alcohol or other central nervous system (CNS) depressants should be avoided due to the risk of potentiating the decrease in alertness and impairment of CNS performance.

Cases of drowsiness have been reported following administration of RYALTRIS in clinical studies (see section Adverse effects).

Antihistaminic effects

Concomitant use of olopatadine (e.g. eye drops) or other antihistamine medicinal products administered nasally, ocularly or orally may increase the risk of antihistaminic adverse effects.

Paediatric population

It is recommended to measure the height of children receiving long-term treatment with intranasal corticosteroids regularly. If growth is slowed, treatment should be reviewed with the aim of reducing the intranasal corticosteroid dose, if possible, to the lowest dose at which effective symptom control is maintained. In addition, referral of the patient to a paediatrician should be considered.

Excipients:

Each spray of RYALTRIS contains 0,02 mg of benzalkonium chloride. Benzalkonium chloride may cause irritation or swelling inside the nose, especially with prolonged use.

No interaction studies have been performed with RYALTRIS.

All drug interactions resulting from the combination of olopatadine and mometasone furoate should be expected to reflect those of the individual components, as no pharmacokinetic interaction between olopatadine and mometasone furoate was observed when administered concomitantly.

Olopatadine :

No interaction between olopatadine and other medicinal products is expected (see section Pharmacokinetics).

Mometasone furoate :

Concomitant treatment with CYP3A inhibitors, including products containing cobicistat, is expected to increase the risk of systemic adverse effects. This combination should be avoided unless the benefit outweighs the increased risk of systemic corticosteroid adverse effects, in which case patients should be monitored for systemic corticosteroid adverse effects.

Pregnancy

Mometasone furoate:

There are no or limited data on the use of mometasone furoate in pregnant women. Animal studies have shown reproductive toxicity (see section Preclinical safety).

Olopatadine :

There are no or limited data on the use of intranasal olopatadine in pregnant women.

Animal studies have shown reproductive toxicity following systemic administration (see section Preclinical safety).

RYALTRIS should not be used during pregnancy unless the potential benefit to the mother justifies the potential risk to the mother, the foetus or the newborn. Newborns whose mothers received corticosteroids during pregnancy should be carefully monitored for possible hypoadrenalism.

Breast-feeding

Mometasone furoate:

It is not known whether mometasone furoate is excreted in human milk.

Olopatadine:

Available animal data show excretion of olopatadine in milk following oral administration (for further information, see section Preclinical safety). A risk to the newborn/infant cannot be excluded.

A decision must be made whether to discontinue breast-feeding or to discontinue/not initiate treatment with RYALTRIS, taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

There are only limited data regarding fertility.

There are no clinical data on the effect of mometasone furoate on fertility. Animal studies have shown reproductive toxicity but no effect on fertility.

There are no clinical data on the effect of olopatadine on fertility.

In isolated cases, treatment with RYALTRIS may cause dizziness, lethargy and fatigue. In these cases, the ability to drive vehicles and use machines may be reduced. Alcohol may potentiate this effect.

Summary of the safety profile

The adverse reactions most frequently reported during treatment with RYALTRIS were dysgeusia (a substance-specific unpleasant taste), epistaxis and nasal discomfort.

Tabulated list of adverse reactions

The following adverse reactions have been reported in clinical studies and post-marketing surveillance 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 < 1/1 000), very rare (< 1/10 000), or frequency not known (cannot be estimated from the available data).

Frequency	Common	Uncommon	Rare	Frequency not known
System organ class
Infections and infestations			Bacterial vaginosis	Pharyngitis* Upper respiratory tract infection*
Immune system disorders				Hypersensitivity, including anaphylactic reactions, angioedema, bronchospasm and dyspnoea*
Psychiatric disorders			Anxiety Depression Insomnia
Nervous system disorders	Dysgeusia (unpleasant taste)	Dizziness Headache Somnolence	Lethargy Migraine
Eye disorders			Blurred vision Dry eye Eye discomfort	Cataract* Glaucoma* Intraocular hypertension*
Ear and labyrinth disorders			Earache
Respiratory, thoracic and mediastinal disorders	Epistaxis Nasal discomfort	Nasal dryness	Nasal inflammation Nasal mucosa disorder Oropharyngeal pain Sneezing Throat irritation	Perforation of the nasal septum*
Gastrointestinal disorders		Dry mouth Abdominal pain Nausea	Constipation Glossalgia
General disorders and administration site conditions		Fatigue
Injury, poisoning and procedural complications			Laceration

* reported with the use of corticosteroids.

Systemic effects of certain intranasally administered corticosteroids may occur, particularly when administered at high doses over prolonged periods (see section Warnings and precautions).

Paediatric population

Growth retardation has been reported in children receiving intranasal corticosteroids. Growth retardation may also be possible in adolescents (see section Warnings and precautions).

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: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

No overdose reactions are anticipated with the intranasal route of administration.

No human data are available regarding overdose by accidental or deliberate ingestion.

Inhalation or oral administration of excessive doses of corticosteroids may lead to suppression of HPA axis function.

There are no known specific antidotes to the active substances of RYALTRIS.

In case of overdose, appropriate monitoring and symptomatic treatment of the patient should be implemented.

Pharmacotherapeutic class: Decongestants and other nasal preparations for topical use, combinations of corticosteroids/mometasone, ATC code: R01AD59.

Mechanism of action and pharmacodynamic effects

RYALTRIS contains olopatadine hydrochloride and mometasone furoate, which have different modes of action and exhibit synergistic effects in terms of improving the symptoms of allergic rhinitis.

Olopatadine is a potent selective antiallergic/antihistaminic agent that exerts its effects through several distinct mechanisms of action. It blocks the action of histamine (the main mediator of the allergic response in humans).

Mometasone furoate is a topical glucocorticoid that possesses anti-inflammatory properties.

It is likely that a significant part of the mechanism responsible for the antiallergic and anti-inflammatory effects of mometasone furoate lies in its ability to inhibit the release of mediators of allergic reactions. Mometasone furoate significantly inhibits the release of leukotrienes by leukocytes from allergic patients. In cell cultures, mometasone furoate has been shown to be extremely potent in inhibiting the synthesis and release of IL-1, IL-5, IL-6 and TNFα ; it is also a potent inhibitor of leukotriene production. Furthermore, it is an extremely potent inhibitor of the production of Th2 cytokines, IL-4 and IL-5, by human CD4+ T lymphocytes.

Clinical efficacy and safety

During 2 clinical studies (GSP 301-301 and GSP 301-304) conducted in adults and adolescents aged 12 years or older with allergic rhinitis, two sprays of RYALTRIS in each nostril twice daily improved nasal symptoms (namely, rhinorrhea, nasal congestion, sneezing and nasal itching) compared with placebo, olopatadine hydrochloride alone and mometasone furoate alone. Onset of action was observed within 15 minutes, defined as the first time point after treatment initiation at which Ryaltris showed a statistically significant and clinically relevant change from baseline for the instantaneous total nasal symptom score (namely rhinorrhea, nasal congestion, sneezing and nasal itching) compared with placebo. The results of these two clinical studies are summarized in Table 1 and Table 2 below.

Table 1: Mean change from baseline in total nasal symptom scores over 2 weeks* in adults and adolescents aged at least 12 years with seasonal allergic rhinitis in study GSP 301-301 (full analysis set)

		Baseline values	Change from baseline	Treatment difference attributable to RYALTRIS
Treatment (2 sprays/nostril twice daily)	N	Mean	Least squares mean	Least squares mean	CI at 95 %	p-value
RYALTRIS	299	10,1	-3,48	--	--	--
Placebo	283	10,2	-2,50	-0,98	(-1,38 ; -0,57)	< 0,0001
Olopatadine hydrochloride	294	10,3	-2,87	-0,61	(-1,01 ; -0,21)	0,0029
Mometasone furoate	294	10,2	-3,09	-0,39	(-0,79 ; 0,01)	0,0587

Table 2: Mean change from baseline in total nasal symptom scores over 2 weeks* in adults and adolescents aged at least 12 years with seasonal allergic rhinitis in study GSP 301-304 (full analysis set)

		Baseline values	Change from baseline	Treatment difference attributable to RYALTRIS
Treatment (2 sprays/nostril twice daily)	N	Mean	Least squares mean	Least squares mean	CI at 95 %	p-value
RYALTRIS	291	10,09	-3,52	--	--	--
Placebo	290	10,32	-2,44	-1,09	(-1,49 ; -0,69)	< 0,001
Olopatadine hydrochloride	290	10,16	-3,08	-0,44	(-0,84 ; -0,05)	0,028
Mometasone furoate	293	10,20	-3,05	-0,47	(-0,86 ; -0,08)	0,019

* Mean of rTNSS (morning and evening) for each day (maximum score = 12) over the 2-week treatment period.

† p-values are nominal

CI = confidence interval; LS = least squares; rTNSS = reduction in total nasal symptom score

Absorption

Following repeated intranasal administration of 2 sprays per nostril of RYALTRIS (2 400 micrograms of olopatadine and 100 micrograms of mometasone furoate) twice daily to patients with seasonal allergic rhinitis, the mean (± standard deviation) maximum plasma exposure (C_max) 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 entire dosing regimen (AUC_tau) was 88,77 ± 23.87 ng*h/mL for olopatadine and 58,40 ± 27,00 pg*h/mL for mometasone furoate. The median time to maximum exposure after single-dose administration was 1 hour for olopatadine and for mometasone furoate.

There was no indication of pharmacokinetic interactions between mometasone furoate and olopatadine hydrochloride.

Distribution

Protein binding of olopatadine was reported as moderate, at approximately 55% in human serum, and was not concentration-dependent over the range of 0,1 to 1 000 ng/mL. Olopatadine binds mainly to human serum albumin.

In vitro, protein binding for mometasone furoate was 98% to 99% over the concentration range of 5 to 500 ng/mL.

Biotransformation

The small amount of mometasone furoate likely to be ingested and absorbed undergoes extensive hepatic first-pass metabolism.

Olopatadine is not metabolised to a significant extent. Two metabolites, the mono-demethyl and the N-oxide, were detected at low concentrations in the urine.

In vitro studies showed that olopatadine did not inhibit the metabolic reactions involving the isoenzymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4 of cytochrome P-450. These results indicate that olopatadine is unlikely to cause interactions with other active substances administered concomitantly.

Elimination

Absorbed mometasone furoate is extensively metabolised, and the metabolites are excreted in the urine and bile. After nasal administration to healthy volunteers, the half-life of mometasone furoate in plasma was approximately 18 to 20 hours.

Pharmacokinetic studies indicate that after oral administration, the half-life of olopatadine in plasma was approximately 8 to 12 hours, and that elimination occurred mainly by renal excretion. Approximately 60 to 70% of the dose was recovered in the urine as active substance.

After nasal administration to healthy volunteers, the half-life of olopatadine in plasma was approximately 6 to 7 hours.

Hepatic impairment

Olopatadine:

No clinically relevant effect of hepatic impairment is expected on the pharmacokinetics of olopatadine, as it is excreted mainly unchanged in the urine (see section Dosage and administration).

Mometasone furoate:

A study carried out with inhaled mometasone furoate in adults with mild, moderate or severe hepatic impairment showed that maximum plasma concentrations of mometasone furoate appear to increase with the severity of hepatic impairment. However, the number of detectable levels was low (see section Dosage and administration).

Renal impairment

Olopatadine:

As olopatadine is excreted in the urine mainly as unchanged active substance, renal impairment alters the pharmacokinetics of olopatadine to produce a plasma AUC_0-∞ plasma 8 times greater in patients with severe renal impairment (mean creatinine clearance of 13,0 ml/min) compared with healthy adults. After administration of an oral dose of 10 mg to patients undergoing haemodialysis (no urinary output), plasma concentrations of olopatadine were substantially lower on the day of haemodialysis compared with the day without haemodialysis, suggesting that olopatadine may be removed by haemodialysis.

Mometasone furoate:

Given the very small contribution of the urinary route to the total body elimination of mometasone furoate, the effects of renal impairment on the pharmacokinetics of mometasone furoate have not been studied (see section Dosage and administration).

Elderly:

Studies comparing the pharmacokinetics of oral doses of 10 mg of olopatadine in young subjects (mean age 21 years) and elderly subjects (mean age 74 years) did not reveal any notable differences in plasma concentrations (AUC), protein binding or urinary excretion of the unchanged parent molecule and its metabolites.

Olopatadine:

Non-clinical data from conventional studies of safety pharmacology, repeated-dose toxicity, genotoxicity, carcinogenesis, and reproduction and developmental functions revealed no particular risk for humans.

Animal studies showed reduced growth of the suckling offspring of females receiving systemic doses of olopatadine well above the maximum recommended level for intranasal use in humans. Olopatadine was detected in the milk of lactating rats after oral administration.

Mometasone furoate:

No toxicological effect specific to exposure to mometasone furoate has been demonstrated. All effects observed are typical of this class of compounds and are related to the exaggerated pharmacological effects of glucocorticoids.

Preclinical studies demonstrate that mometasone furoate does not exert androgenic, antiandrogenic, oestrogenic or antioestrogenic activity, but that, like other glucocorticoids, it shows some anti-uterotrophic activity and delays vaginal opening in animal models at high oral doses of 56 mg/kg/day and 280 mg/kg/day.

Like other glucocorticoids, mometasone furoate showed clastogenic potential in vitro at high concentrations. However, no mutagenic effect can be expected at relevant therapeutic doses.

In reproductive function studies, subcutaneous administration of mometasone furoate at 15 micrograms/kg prolonged gestation and prolonged, difficult parturition occurred, accompanied by reduced offspring survival and reduced body weight or body weight gain of the pups. There was no effect on fertility.

Like other glucocorticoids, mometasone furoate is teratogenic in rodents and rabbits. The effects observed were umbilical malformations in rats, cleft lip in mice, and agenesis of the gallbladder, umbilical hernias and flexed forelimbs in rabbits. Reductions in maternal body weight gain, effects on foetal growth (reduced foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice were also noted.

The carcinogenic potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0,25 to 2,0 micrograms/l was studied in 24-month studies in mice and rats. Effects typical of glucocorticoids, including several non-neoplastic lesions, were observed. No notable dose-response relationship was detected for any of the tumour types.

RYALTRIS Nasal spray:

A study of repeated intranasal administration of RYALTRIS to rats for a maximum period of 13 weeks did not reveal any new adverse effects compared with the individual components.

Environmental risk assessment (ERE)

Environmental risk assessment studies showed that mometasone furoate may pose a risk to the aquatic environment (see section Disposal and handling).

3 years

Shelf life after opening (after first use): 2 months

Do not freeze.

This medicine may present a risk to the environment (see section Preclinical safety).

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

List I

Marketing authorisation (AMM)

CIP 3400930240595 (Fl/30ml).

Price:

10,23 euros (Fl/30ml).

Reimbursed by Social Security at 30% and Collective in the indication "in adults and adolescents aged 12 years and older, for the treatment of moderate to severe nasal symptoms of allergic rhinitis, as second-line therapy, when monotherapy with an antihistamine or intranasal corticosteroid is not considered sufficient."

 

Marketing Authorisation Holder : Glenmark Pharmaceuticals S.R.O. Hvezdova 1716/2B, Prague 4, 140 78. Czech Republic.