Introduction

Allergic rhinitis (AR) is very frequently caused by pollen from grasses, herbs, and trees or animal dander, house dust mites and molds, although the prevalence varies considerably in different regions of Europe and the world [1, 2]. The prevalence is clearly age-dependent. In a birth cohort study, the sensitization rate to Phleum pratense was 9.7% at the age of 4 years, 28.4% at the age of 8 years, and 37.1% at the age of 16 years [3]. It has long been known that the prevalence of AR peaks in the second to fourth decade of life [4]. Furthermore, AR is a known risk factor for the development of bronchial asthma, and vice versa this comorbidity is significantly increased [2, 5,6,7].

Typical symptoms of AR include rhinorrhea, nasal congestion, sneezing, and itching [8, 9]. Furthermore, itching and redness of the conjunctiva as well as lacrimation, itching of the throat, oral mucosa, and external auditory canals can occur, as well as non-specific symptoms such as a general feeling of illness, weakness, tiredness and fatigue, and sleep disturbances [2, 10]. These symptoms can have a negative impact on quality of life and/or performance at work and school [11, 12].

Traditionally, AR is divided into a seasonal and perennial form depending on seasonal (mainly outdoor) allergens present in the patient’s environment such as pollen or perennial (mainly indoor) allergens such as house dust mites, animal dander, and mold spores.

However, these terms can be contradictory, as the symptoms of seasonal allergies can be present for several months of the year and the concentrations of year-round allergens can change seasonally [13,14,15].

Seasonal and perennial AR can occur side by side, with symptoms increasing in severity during certain seasons and up to 80% of patients exhibiting a mixed form [13, 14]. Therefore, a new classification into intermittent and persistent allergic rhinitis is used today [2, 16]. The new definition does not take into account the type of triggering allergen primarily, but the duration of symptoms [16]. This classification was adapted to the German healthcare system [2]. A validation study of the ARIA classification in France found that approximately 43.7% of patients with seasonal AR actually had persistent rhinitis, while 44.6% of patients classified as having perennial AR could be classified as having intermittent rhinitis [17], which was confirmed in further studies in Germany and Western Europe [18, 19]. For therapy, it is important to note that patients with seasonal AR can also suffer from long-term symptoms over several seasons and that perennial allergic rhinitis does not necessarily mean that the patient has symptoms all year round, but that it can also be intermittent [20, 21].

Several mediators are involved in the pathophysiology of AR. In the early reaction phase (within minutes after exposure), inflammatory mediators from mast cells such as histamine, cytokines, leukotrienes, and prostaglandins are essential [22]. These mediators are responsible for clinical symptoms such as nasal congestion, sneezing, itching, and/or rhinorrhea. In the late phase (after hours), there is an influx of inflammatory cells such as eosinophils, basophils, monocytes, and neutrophils, which release interleukins and can lead to long-lasting or chronic symptoms.

Treatment options for allergic rhinitis

The treatment of AR includes avoiding contact with the triggering allergen (allergen avoidance), pharmacotherapy, allergen immunotherapy, and non-pharmacological treatment options [1, 2, 23]. As allergen avoidance is often not possible, pharmacotherapy is the mainstay of treatment in the current situation of symptomatic disease [1].

Pharmacotherapy of AR

Medications used in the pharmacotherapy of AR primarily include INCS, intranasal and oral AH, leukotriene antagonists, intranasal cromoglicic acid preparations, intranasal and oral vasoconstrictors, and nasal rinses [1, 8, 10, 15].

The ARIA guideline for the German healthcare system [2] recommends INCS as first-line therapy for patients with intermittent and persistent AR and considers them to be the treatment of first choice for any form of AR due to their superior efficacy and tolerability [2, 15]. There is no clear evidence of differences in the efficacy of individual INCS compared to others [24, 25], but there are clear differences in the systemic bioavailability of INCS [1]. The systemic bioavailability of mometasone furoate, ciclesonide, fluticasone furoate, and fluticasone propionate is the lowest among currently available INCS [23], minimizing the risk of systemic adverse events [26]. Increasing the INCS dose does not provide any additional symptomatic benefit due to the flat dose–response curves. In fact, a threshold for the efficacy of INCS has now been established [27]. In patients with mild-to-moderate disease, oral or intranasal H1 antihistamines (AH) may also be effective, but these usually do not have sufficient potency in patients with severe disease [1]. Data from practice confirm that INCS are superior to oral H1-AH in all patient groups with AR [2, 28]. Rupatadine [29] and bilastine [30] can be described as the latest generation of oral AHs.

As with all medications, side effects are also possible with AR therapy. The greatest risk comes from systemic glucocorticosteroids, which must be reserved for the most severe cases. A recently published consensus paper from the European Academy of Allergology and Clinical Immunology (EAACI) addresses the use of systemic glucocorticosteroids in the treatment of upper respiratory tract disease, highlights the potential harms of this therapy, and makes recommendations for their very cautious use [31]. Although less common and less severe than systemic glucocorticosteroids, oral AHs are also associated with adverse effects [32, 33].

In this situation and in view of the OTC availability of many antiallergic drugs, many patients combine different drugs such as nasal and oral AH, leukotriene receptor antagonists, mast cell stabilizers, and INCS [34,35,36].

However, this form of polypharmacy, such as the free combination of a nasal AH with an INCS, provides little or no symptomatic benefit compared to INCS monotherapy [37, 38].

This is due to the mismatched pharmacological or pharmacodynamic properties of these therapies [10]. For example, INCS is in a lipophilic solution and nasal AH is in a hydrophilic solution. This means that if INCS is applied, a subsequent AH application has no effect because the INCS application forms a fine lipid layer on the mucous membrane and the AH can no longer penetrate the cells to have an effect. Therefore, many patients cannot adequately treat their symptoms with the available monotherapies or their free combination [36, 39] and are not surprisingly dissatisfied with the symptomatic relief achieved [40].

Fixed combinations of INCS and intranasal H1-AHs are an innovative treatment option in this situation. They combine the advantages of H1-AHs (rapid onset of action) with those of INCS (strong, sustained efficacy, good effect also against nasal obstruction) and are also very effective in patients with severe symptoms [2, 10]. To date, only one preparation, a combination of azelastine and fluticasone [41], was available on the market in Germany. Recently, an alternative was added with an olopatadine and mometasone combination nasal spray, whose efficacy in all forms of moderate-to-severe AR was demonstrated in a meta-analysis [42].

The use of pharmacotherapies is an effective option for immediate relief of AR symptoms. However, in a survey conducted by the American Academy of Otorhinolaryngology–Allergy, 47% of AR patients taking at least one prescription medication reported using at least two or more prescription medications plus one over-the-counter medication to treat their symptoms [11]. Taking multiple medications can increase healthcare costs and result in medication dosage recommendations not being met. For effective treatment of AR symptoms, medications that provide both rapid and sustained symptom relief and have minimal side effects are important [11]. Monopreparations of AH and INCS have been the mainstay therapy for AR. Therefore, it stands to reason that a combination of a fast-acting intranasal AH and a long-lasting and potent INCS would provide more effective symptom control than monotherapy [43, 44]. The use of a single combination nasal spray for AR treatment rather than the free combination of multiple monotherapies could have the added benefit of reducing costs [45] and improving adherence [46, 47].

Fixed combinations of INCS and intranasal H1-AHs as nasal sprays

Fixed combination azelastine hydrochloride/fluticasone propionate nasal spray (MP-AzeFlu)

MP-AzeFlu was introduced as the first fixed combination of intranasal AH (azelastine hydrochloride) and INCS (fluticasone propionate) in a novel formulation as a nasal spray for AR therapy. The results of well-designed randomized controlled trials (RCTs) showed that patients with moderate-to-severe seasonal AR (SAR) treated with MP-AzeFlu experienced a rapid onset of relief (i.e., 30 min) and 20–30% more effective treatment of nasal and ocular symptoms compared to INCS treatment alone, and twice as much relief as with an intranasal AH [27, 48, 49]. In addition, more MP-AzeFlu patients (SAR and PAR) experienced complete or near-complete relief of symptoms [50,51,52,53,54,55,56]. Side effects such as nosebleeds can occur very frequently (in more than one in ten patients), while headache, bitter taste, and an unpleasant odor can occur frequently (in up to one in ten patients). Side effects such as irritation/dryness of the nose, throat, and/or mouth may occur occasionally to rarely, while dizziness or drowsiness, cataract, glaucoma, damage to the skin/mucous membrane, feeling sick, faint, exhausted or weak, skin rash, bronchospasm may occur very rarely.

MP-AzeFlu has been available as a nasal spray on the European market since 2013 and can be considered an established treatment option for AR.

Fixed combination olopatadine hydrochloride/mometasone furoate monohydrate nasal spray (Olo-Mom)

In January 2022, the US Food and Drug Administration (FDA) approved olopatadine hydrochloride and mometasone furoate monohydrate nasal spray (Olo-Mom) for the treatment of AR symptoms in patients aged 12 years and older [57, 58]. On their own, olopatadine (ophthalmic) and mometasone (nasal) are effective and well tolerated agents for the treatment of AR [59,60,61,62]. Similar to the individual components as monotherapies, the combination of Olo-Mom is also approved for AR. However, there are differences in terms of the onset and duration of action [58].

The aim of this review is to evaluate the available literature on the pharmacology, efficacy, and safety of Olo-Mom in the treatment of AR and to make recommendations for its use in the German healthcare system.

Methodology

In a literature search in Medline, PubMed, as well as the national and international study (ClinicalTrials.gov) and guideline registers and the Cochrane Library, treatment options for AR were analyzed and the available evidence was determined. Human studies published on the topic in the period up to and including August 2023 were taken into account. Particular emphasis was placed on the new fixed combination of mometasone and olopatadine and its laboratory code GSP301. Prospective clinical studies, meta-analyses, systematic reviews, and review articles in German and English were considered.

Results

The search results revealed 14 scientific articles on the new fixed combination of mometasone and olopatadine, and six clinical trials were also identified in ClinicalTrials.gov.

The analyses of these articles and study descriptions are presented here.

Clinical pharmacology of the Olo-Mom nasal spray

Olo-Mom is a fixed combination of the AH olopatadine hydrochloride and the glucocorticosteroid mometasone furoate. Olopatadine has a dual action as a selective AH with mast-cell-stabilizing properties. Olopatadine acts as an AH by binding to and stabilizing mast cells and leads to an inactive conformation of histamine 1 (H1) receptors [63]. Through a transcription factor known as nuclear factor κ B, olopatadine’s effect on inflammation also decreases antigen presentation, expression of proinflammatory cytokines and cell adhesion molecules, and chemotaxis [63]. Furthermore, olopatadine can stabilize mast cells, which leads to the inhibition of mast cell activation and histamine release [63].

Mometasone is a glucocorticosteroid with a strong anti-inflammatory effect. The binding between glucocorticosteroids and glucocorticosteroid receptors in the cytoplasm creates a complex that penetrates the cell nucleus and regulates the expression of pro-inflammatory and anti-inflammatory genes [64, 65]. Mometasone inhibits the expression of genes responsible for the development and maintenance of inflammation, the production of proinflammatory cytokines, and the expression of adhesion molecules.

Pharmacokinetics

Given the combination of two active ingredients in the Olo-Mom product, two open-label, single-dose crossover studies were conducted to determine the pharmacokinetics for optimal Olo-Mom dosing [66, 67]. The results of both studies showed that the combination of olopatadine and mometasone in Olo-Mom had no significant effect on the pharmacokinetics of either drug compared to their monotherapies [57, 66, 67].

The protein binding of olopatadine is 55%, and interactions due to displacement from plasma proteins are not expected [57, 68].

Studies have shown that mometasone is primarily and extensively metabolized in the liver of all species studied and undergoes extensive metabolism to several metabolites [57].

In vitro studies have confirmed the primary role of cytochrome CYP3A4 in the metabolism of mometasone [69]. In one study, an increase in mometasone plasma concentrations was demonstrated after concomitant administration of ketoconazole, a strong CYP3A4 inhibitor [69]. These clinically relevant effects are highly unlikely in view of the intranasal administration of mometasone with low systemic absorption.

Dosage and administration

Different doses of Olo-Mom were investigated in two phase II studies. Once-daily (olopatadine 665 µg + mometasone 50 µg) Olo-Mom treatment and twice-daily administration (olopatadine 665 µg + mometasone 50 µg) were compared with either placebo or a comparator [70, 71], with either one spray [71] or two sprays [70] administered per nostril. The twice-daily administration of Ole-Mom with two sprays per nostril showed a significant and clinically meaningful improvement in the rTNSS (Reflected Total Nasal Symptom Score) compared to the two monotherapies [70]. This regimen was used for the phase III studies as this dosage met the regulatory threshold for fixed-dose combinations. The results are shown in Table 1.

Table 1 Summary of clinical studies evaluating the efficacy of olopatadine hydrochloride mometasone furoate (Olo-Mom; from [70,71,72,73], modified after [58])
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Clinical studies

The efficacy of Olo-Mom in the treatment of AR was tested in two double-blind, randomized, placebo-controlled phase II studies (NCT03444506 [71] and NCT02318303 [70]) and three phase III studies (NCT02870205 [72], NCT02631551 [73], and NCT02709538 [74]).

The primary endpoints assessed in each clinical trial were either the iTNSS (Instantaneous Total Nasal Symptom Score) and/or the rTNSS (Reflective Total Nasal Symptom Score). The secondary endpoints measured in each clinical trial consisted of the Reflective Total Ocular Symptom Score (rTOSS), the Instantaneous Total Ocular Symptom Score (iTOSS), the RQLQ(S) Score of the Rhinoconjunctivitis Quality of Life Questionnaire, treatment-emergent adverse events (TEAEs) and/or the onset of action (OOA). OOA was determined if there was a sustained significant difference in the change in iTNSS score from baseline over the measured time interval.

Phase II studies

The first phase II study, NCT03444506, by Patel et al. [71] used a ragweed pollen exposure chamber (EEC) model to evaluate the efficacy and safety of a once- or twice-daily administration of one spray per nostril for 14 days compared to placebo and two approved nasal sprays, olopatadine and a fixed combination of azelastine hydrochloride and fluticasone propionate (MP-AzeFlu). The EEC study allowed for constant exposure to the allergen throughout the study and continuous monitoring of participants’ adherence to treatment compared to natural allergen exposure studies [75]. Twice-daily and once-daily administration of Olo-Mom showed statistically significant improvements in iTNSS compared to placebo (p < 0.0001 for twice-daily and once-daily; [71]). There was no statistically significant difference between Olo-Mom twice daily (p = 0.12) and once daily (p = 0.44) compared to azelastine and fluticasone. The study showed that Olo-Mom twice daily and once daily improved SAR symptoms compared to placebo.

Another phase II study conducted by Andrews et al. (NCT02318303; [70]) investigated the efficacy and safety of twice-daily and once-daily Olo-Mom compared to placebo and twice-daily and once-daily olopatadine and mometasone monotherapy, each with two sprays per nostril for 14 days. Twice-daily Olo-Mom resulted in a statistically significant and clinically meaningful improvement (difference of > 0.23 units) in rTNSS compared to placebo (p < 0.001), twice-daily olopatadine (p = 0.049), and mometasone (p = 0.004; [70]).

Phase III studies

Three phase III clinical trials were conducted. Two with SAR and one with PAR led to FDA approval of Olo-Mom (Table 1).

The phase III study (NCT02870205) conducted by Gross et al. was a 14-day randomized, double-blind, placebo-controlled study with participants older than 12 years of age who had been suffering from moderate-to-severe SAR for at least 2 years. The 1176 participants were randomized into four treatment groups: twice-daily Olo-Mom, olopatadine monotherapy, mometasone monotherapy, or placebo. Compared to placebo, olopatadine monotherapy, and mometasone monotherapy, Olo-Mom showed statistically significant and clinically meaningful rTNSS improvements in the treatment of SAR-associated nasal symptoms in all patients aged 12 years and older (p < 0.001, p < 0.03, and p < 0.02, respectively; Fig. 1; [72]). The overall results showed that the improvement in nasal symptoms with Olo-Mom was rapid, with an onset of action of 15 min, and persisted throughout the 14-day treatment period, demonstrating the efficacy of the product in both acute and late allergic reactions.

Fig. 1
figure 1

Comparison of the Reflective Total Nasal Symptom Score (rTNSS) after 14 days of treatment with placebo. Olo-Mom olopatadine hydrochloride/mometasone furoate monohydrate, LSMD least mean square difference. (Modified after [72])

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The phase III study, NCT02631551, conducted by Hampel et al. was a 14-day randomized, double-blind, placebo-controlled study with participants who had been suffering from moderate-to-severe SAR for at least 2 years. A total of 1180 participants were randomized into four treatment groups: twice-daily Olo-Mom, olopatadine monotherapy, mometasone monotherapy, or placebo. The results showed that Olo-Mom had a statistically significant mean improvement in rTNSS compared to placebo and olopatadine monotherapy [73]. Olo-Mom compared to mometasone approached, but did not reach, the mean rTNSS improvements in a statistically significant manner. Olo-Mom confirmed an onset of action after 15 min that persisted over the entire 14-day treatment period.

Segall et al. conducted a study on PAR (NCT02709538). This is a 52-week phase III study with 601 patients older than 12 years and a history of PAR of at least 2 years. Patients were randomized into three treatment groups (olopatadine-mometasone twice daily [665 µg/25 µg], placebo pH 3.7 or placebo pH 7.0). The primary endpoint was the safety of the drug in long-term use and the effect of pH on nasal comfort. Twice-daily olopatadine mometasone (665 µg/25 µg) was well tolerated and led to statistically significant and clinically meaningful improvements in PAR nasal symptoms without the occurrence of tachyphylaxis compared to placebo over 52 weeks [74].

Safety aspects

Adverse drug reactions (ADRs) were described in connection with the use of Olo-Mom on the basis of pooled data (N = 1580) from the studies by Segall et al. [74], Gross et al. [72], and Hampel et al. [73]. The most common ADRs (incidence ≥ 1%) observed with the use of Olo-Mom were dysgeusia and epistaxis [57, 72,73,74]. Anaphylactic reactions were not observed in clinical studies. A decrease in efficacy was also not observed over 52 weeks [74]. The use of Olo-Mom in pregnancy has not been studied; therefore, the estimated risk of treatment with this drug is not known.

There is also insufficient experience in breastfeeding. There are no data on the presence of olopatadine or mometasone or its metabolites in breast milk that could have an effect on the breastfed child or the effects on milk production [57].

While studies with older INCS suggested a reduction in growth velocity in children, newer INCS apparently have no negative effect here [57, 76].

The use of Olo-Mom is generally contraindicated in patients with a known hypersensitivity to any of the ingredients, in particular mometasone furoate and/or olopatadine hydrochloride. Patients should be monitored regularly for local nasal side effects such as epistaxis, nasal ulceration, and nasal septal perforation. Hypercorticism and adrenal suppression may occur with inappropriate use or use of higher-than-recommended doses or regular dosing in high-risk patients [57].

Relevance for patient care and clinical practice

Current guidelines recommend intranasal antihistamines (INAH) for the initial treatment of SAR, especially in mild cases [77]. However, for persistent symptoms of AR and particularly severe nasal obstruction, INCS are recommended as the preferred medication [77]. Based on these two recommendations, the guidelines recommend the combination of an INCS and an INAH for the initial treatment of moderate AR in patients aged 12 years and older with persistent symptoms who have not responded to monotherapy [77]. This could be primarily due to the differences in the onset and duration of action of INAH and INCS.

It has been shown that INAHs are effective in the treatment of nasal symptoms, but have weaknesses in their efficacy profile, particularly in nasal congestion [4]. Data from phase III studies show that the onset of action of the combination drug was around 15 min, most likely due to the fact that the onset of action of olopatadine as INAH is between 15 and 30 min [72, 73]. In addition, INAH has the advantage that the drug is delivered specifically to the nasal tissue and thus systemic effects are limited [78].

Furthermore, INCS have also demonstrated efficacy on all nasal symptoms of AR in numerous placebo-controlled clinical trials [4, 79]. In addition, INCS have had a positive effect on ocular AR symptoms [4, 80]. A significant improvement in sleep and quality of life has also been demonstrated [4, 81]. In both phase III studies on SAR, the Olo-Mom effects persisted over the entire 14-day treatment period [72, 73].

The combination of olopatadine and mometasone makes it possible to utilize the rapid onset of action of an INAH and the long duration of action of an INCS in a single product. Although the use of a combination product increases the risk of adverse effects [82], all clinical studies individually showed no statistically significant difference in the occurrence of adverse effects of the combination product compared to its individual components [72, 73]. A systematic meta-analysis of the two phase II and three phase III studies on Olo-Mom [42] showed statistically significant improvements in rTNSS and iTNSS as well as an improvement in rTOSS and iTOSS [42].

The intranasal fixed combinations of glucocorticosteroid and AH azelastine/fluticasone nasal spray (Aze-Flu) and olopatadine-mometasone nasal spray (Olo-Mom) do not appear to show any significant differences in terms of efficacy and safety [83]. However, an anchored best-worst scaling (ABWS) method was used to analyze how patients rate the treatment characteristics of the current combination nasal sprays. To do this, 426 adults in Australia with moderate-to-severe AR who used either Olo-Mom or Aze-Flu nasal sprays were asked in an online survey about 11 domains, seven of which were sensory (direct taste of medication, aftertaste of medication, smell of medication, nasal irritation, sneezing irritation, drip from nose/throat, dryness of nose/throat) and four treatment-related criteria (convenience, rapid onset of action, duration of action, and control of AR symptoms).

Participants who used Olo-Mom were significantly more satisfied than participants who used Aze-Flu in seven out of 11 areas (all p < 0.05). The preferred areas were predominantly the sensory properties of the products. The authors encourage prescribers of AR treatments to discuss with their patients which characteristics they value in the treatment so as to facilitate shared decision-making. The AR patients who value sensory properties in their treatment may benefit from using the Olo-Mom nasal spray as they are likely to be more satisfied with their treatment, which may increase adherence [83]. On the other hand, MP-AzeFlu would benefit patients who are somewhat more lax in its precise application, as only one spray per nostril is required twice daily [84].

Discussion

The treatment of AR comprises a variety of measures, which classically include allergen immunotherapy in addition to allergen avoidance and pharmacotherapy. Non-pharmacological measures are mainly used for allergen avoidance. Medications used in the pharmacotherapy of AR include INCS, intranasal and oral AH, leukotriene antagonists, intranasal cromoglicic acid preparations, intranasal and oral vasoconstrictors, and nasal rinses [1, 2, 10]. With sufficient penetration of the epithelial layer, topical application of the medication can achieve considerably higher concentrations in the airway mucous membranes than systemic administration, and the effect is often more rapid [1]. With significantly reduced concentrations in the blood and total body dose, topical therapies (nasal sprays) are therefore preferable to systemic application.

Fixed combinations of INCS and INAH as nasal sprays represent a significant and decisive advance in the treatment of moderate-to-severe AR [1, 2, 77]. Although treatment-related side effects may be slightly increased with the fixed combinations, fixed combinations provide significant symptom relief for patients who do not respond well or at all to the individual preparations and substantially improve their quality of life [82].

For the fixed combination Olo-Mom, data from several phase II and III clinical trials show significant improvements in AR symptoms. In patients aged 12 years and older, Olo-Mom can be considered as first-line treatment for moderate AR with persistent symptoms despite monotherapy. In terms of patient satisfaction, Olo-Mom could have advantages over the otherwise also very effective fixed combination spray Aze-Flu and thus possibly increase patient satisfaction and thereby treatment adherence [83].