Source: Health Products Regulatory Authority (IE) Revision Year: 2021 Publisher: Glenmark Pharmaceuticals s.r.o, Hvezdova 1716/2b, Prague 4, 140 78, Czech Republic
Pharmacotherapeutic group: Decongestants and other nasal preparations for topical use, corticosteroids/mometasone, combinations
ATC code: R01AD59
Ryaltris contains olopatadine hydrochloride and mometasone furoate, which have different modes of action and show synergistic effects in terms of improvement of allergic rhinitis symptoms.
Olopatadine is a potent selective antiallergic/antihistaminic agent that exerts its effects through multiple distinct mechanisms of action. It antagonises histamine (the primary mediator of allergic response in humans).
Mometasone furoate is a topical glucocorticosteroid with local anti-inflammatory properties. It is likely that much of the mechanism for the anti-allergic 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 from leucocytes of allergic patients. In cell culture, mometasone furoate demonstrated high potency in inhibition of synthesis and release of IL-1, IL-5, IL-6 and TNFα; it is also a potent inhibitor of leukotriene production. In addition, it is an extremely potent inhibitor of the production of the Th2 cytokines, IL-4 and IL-5, from human CD4+ T-cells.
In 2 clinical studies (GSP 301-301 and GSP 301-304) in adults and adolescents 12 years of age or older with allergic rhinitis, Ryaltris two sprays in each nostril twice daily improved nasal symptoms (comprising rhinorrhoea, nasal congestion, sneezing and nasal itching) compared with placebo, olopatadine hydrochloride alone and mometasone furoate alone. The results of the two clinical studies are summarised in the Table 1 and Table 2 below.
Table 1. Mean Change from Baseline in Reflective Total Nasal Symptom Scores Over 2 Weeks* in Adults and Adolescents Aged ≥12 Years with Seasonal Allergic Rhinitis in Study GSP 301-301 (full analysis set):
| Baseline | Change From Baseline | Ryaltris Treatment Effect Difference | ||||
|---|---|---|---|---|---|---|
| Treatment (2 sprays/nostril twice daily) | N | Mean | LS Mean | LS Mean | 95% CI | Pvalue† |
| Ryaltris | 299 | 10.1 | -3.48 | -- | -- | -- |
| Placebo | 283 | 10.2 | -2.50 | -0.98 | (-1.38, -0.57) | <0.0001 |
| Olopatadine HCl | 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 Reflective Total Nasal Symptom Scores Over 2 Weeks* in Adults and Adolescents Aged ≥12 Years with Seasonal Allergic Rhinitis in Study GSP 301-304 (full analysis set):
| Baseline | Change From Baseline | Ryaltris Treatment Effect Difference | ||||
|---|---|---|---|---|---|---|
| Treatment (2 sprays/nostril twice daily) | N | Mean | LS Mean | LS Mean | 95% CI | P-value† |
| Ryaltris | 291 | 10.09 | -3.52 | -- | -- | -- |
| Placebo | 290 | 10.32 | -2.44 | -1.09 | (-1.49, -0.69) | <0.001 |
| Olopatadine HCl | 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 |
* Average of AM and PM rTNSS for each day (maximum score = 12) and averaged over the 2-week treatment period.
† P-values are nominal
CI= confidence interval; LS= least square;
After repeated intranasal administration of 2 sprays per nostril of Ryaltris (2400 microgram of olopatadine and 100 microgram 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*hr/mL for olopatadine and 58.40 ± 27.00 pg*hr/mL for mometasone furoate. The median time to peak exposure from a single dose was 1 hour for both olopatadine and mometasone furoate.
There was no evidence of pharmacokinetic interactions between mometasone furoate and olopatadine hydrochloride.
The protein binding of olopatadine was reported as 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.
The small amount of mometasone furoate that may be swallowed and absorbed undergoes extensive first-pass hepatic metabolism.
Olopatadine is not extensively metabolised. Two metabolites, the mono-desmethyl and the N-oxide, were detected at low concentrations in the urine.
In vitro studies have shown that olopatadine did not inhibit metabolic reactions which involve cytochrome P-450 isozymes 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 and 3A4. These results indicate that olopatadine is unlikely to result in metabolic interactions with other concomitantly administered active substances.
Absorbed mometasone furoate is extensively metabolized and the metabolites are excreted in urine and bile. After nasal administration, the half-life of mometasone furoate in plasma was approximately 18 to 20 hours, in healthy volunteers.
From oral pharmacokinetic studies, the half-life of olopatadine in plasma was approximately eight to 12 hours, and elimination was predominantly through renal excretion. Approximately 60-70% of the dose was recovered in the urine as active substance.
After nasal administration, the half-life of olopatadine in plasma was approximately six to seven hours, in healthy volunteers.
No clinically relevant effect of hepatic impairment is expected on the Olopatadine pharmacokinetics since it is predominantly excreted unchanged via urine (see section 4.2).
A study performed with inhaled mometasone furoate in adults with mild, moderate and severe hepatic impairment has shown that peak plasma concentrations of mometasone furoate appear to increase with severity of hepatic impairment, however, the number of detectable levels were few (see section 4.2).
Since olopatadine is excreted in urine primarily as unchanged active substance, impairment of renal function alters the pharmacokinetics of olopatadine with 8-fold greater plasma AUC0-∞ in patients with severe renal impairment (mean creatinine clearance of 13.0 ml/min) compared to healthy adults. Following a 10 mg oral dose in patients undergoing haemodialysis (with no urinary output), plasma olopatadine concentrations were significantly lower on the haemodialysis day than on the nonhaemodialysis day suggesting olopatadine can be removed by haemodialysis.
Due to the very low contribution of the urinary pathway to total body elimination of mometasone furoate, the effects of renal impairment on pharmacokinetics of mometasone furoate have not been investigated (see section 4.2).
Studies comparing the pharmacokinetics of 10 mg oral doses of olopatadine in young (mean age 21 years) and elderly (mean age 74 years) showed no significant differences in the plasma concentrations (AUC), protein binding or urinary excretion of unchanged parent drug and metabolites.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety, pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Studies in animals have shown reduced growth of nursing pups of dams receiving systemic doses of olopatadine well in excess of the maximum level recommended for human intranasal use. Olopatadine has been detected in the milk of nursing rats following oral administration.
No toxicological effects unique to mometasone furoate exposure were demonstrated. All observed effects are typical of this class of compounds and are related to exaggerated pharmacologic effects of glucocorticoids.
Preclinical studies demonstrate that mometasone furoate is devoid of androgenic, antiandrogenic, estrogenic or antiestrogenic activity but, like other glucocorticoids, it exhibits some antiuterotrophic 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 a clastogenic potential in-vitro at high concentrations. However, no mutagenic effects can be expected at therapeutically relevant doses.
In studies of reproductive function, subcutaneous mometasone furoate, at 15 micrograms/kg prolonged gestation and prolonged and difficult labour occurred with a reduction in offspring survival and body weight or body weight gain. There was no effect on fertility.
Like other glucocorticoids, mometasone furoate is a teratogen in rodents and rabbits. Effects noted were umbilical hernia in rats, cleft palate in mice and gallbladder agenesis, umbilical hernia, and flexed front paws in rabbits. There were also reductions in maternal body weight gains, effects on foetal growth (lower foetal body weight and/or delayed ossification) in rats, rabbits and mice, and reduced offspring survival in mice.
The carcinogenicity potential of inhaled mometasone furoate (aerosol with CFC propellant and surfactant) at concentrations of 0.25 to 2.0 micrograms/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.
Repeated dose intranasal toxicity study in rats for a period up to 13 weeks with Ryaltris revealed no new adverse effects in comparison to the individual components.
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