Reviewing the evidence surrounding preservative-free tafluprost/timolol fixed-dose combination therapy in open-angle glaucoma and ocular hypertension management: a focus on efficacy, safety, and tolerability

ABSTRACT

Introduction

Elevated intraocular pressure (IOP) is the most important modifiable risk factor for irreversible sight loss in open-angle glaucoma (OAG). The topical fixed-dose combination (FC) of preservative-free (PF) tafluprost (0.0015%) and timolol (0.5%) (tafluprost/timolol) is among the second-line IOP-lowering options for OAG and ocular hypertension (OHT).

Areas covered

PubMed searches identified publications reporting key evidence from randomized controlled trials (RCTs) and real-world studies examining the safety, tolerability, and IOP-lowering efficacy of PF tafluprost/timolol FC therapy in OAG/OHT management.

Expert opinion

Glaucoma patients are more likely to have ocular surface disease, and treatment should be individualized so that target response may be achieved while considering tolerability and quality of life, according to European Glaucoma Society guidelines. PF FC therapies, such as PF tafluprost/timolol FC, avoid ocular surface exposure to toxic preservative agents and reduce the required number of treatment administrations. These properties may enhance treatment tolerability and adherence, resulting in improved IOP-lowering efficacy and disease control. Treatment outcomes from RCTs and real-world studies examining PF tafluprost/timolol FC therapy support this hypothesis, with significant IOP reductions and/or improvements in tolerability parameters demonstrated, regardless of the prior topical therapy used and even when switched directly to PF tafluprost/timolol FC treatment (without washout).

KEYWORDS:

• Beta-blocker monotherapy
• ocular hypertension
• open-angle glaucoma
• preservative-free topical medication
• real-world evidence
• tafluprost/timolol fixed-dose combination
• prostaglandin analog monotherapy

1. Introduction

The preservative free (PF) fixed-dose combination (FC) of tafluprost (0.0015%) and timolol (0.5%) (PF tafluprost/timolol FC; Santen Oy, Finland) has been available in Europe since 2014 [1]. It is indicated for the reduction of intraocular pressure (IOP) in adult patients with open-angle glaucoma (OAG) or ocular hypertension (OHT) who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogs (PGAs) and require a combination therapy, and who would benefit from PF eye drops [1].

Elevated IOP is the most important modifiable risk factor for disease progression, and irreversible sight loss in OAG and reduction of IOP are believed to slow visual field deterioration [2,3]. Treatment approaches focus on reducing IOP and then maintaining lower pressure over the long term [2,3]. Recommended first- and second-line therapy for OAG/OHT comprises topical IOP-lowering medications, which typically include PGAs and beta-blockers (usually timolol) [2,3]. Local toxicity issues associated with exposure to preservative agents, such as the commonly used benzalkonium chloride (BAK), can affect treatment adherence and lead to poor IOP control [2,4–16]. Ocular surface disease (OSD) is prevalent in people with glaucoma compared with the general population, and the use of topical medications containing preservative agents may exacerbate inflammation, resulting in suboptimal long-term therapeutic and surgical outcomes and reduced quality of life (QoL) [2,12–16].

Glaucoma treatment should be tailored to the individual, balancing powerful IOP reduction and control against good tolerability [2,3,11]. European Glaucoma Society guidelines recommend that treatment should aim to achieve target response using the fewest medications possible while considering inconvenience to the patient, QoL, cost, and side effects [2]. FC treatment is preferable when two or more agents are required to adequately lower IOP, and PF FC formulations offer the benefit of delivering two IOP-lowering agents while avoiding preservative exposure at the ocular surface [2].

This review examines the available evidence from randomized controlled trials (RCTs) and real-world observational studies concerning the use of PF tafluprost/timolol FC therapy in the management of OAG and OHT [17–31]. Studies have demonstrated significant IOP reduction and improved signs of ocular surface health among people with OAG or OHT treated with topical PF tafluprost/timolol FC therapy [17–31]. The evidence discussed herein provides insights regarding the efficacy and tolerability profile of this medication and the ways in which these aspects may influence patient outcomes. The Drug Summary Box (Box 1) summarizes key information regarding the PF tafluprost/timolol FC, including dosing and administration, mechanism of action and the key trials examining its use in the management of OAG/OHT [1,18–20,22,31].

Drug summary box. The preservative-free fixed-dose combination of tafluprost (0.0015%) and timolol (0.5%).

Drug name	PF tafluprost/timolol FC
Phase [1]	Post-authorization
Indication [1]	Reduction of IOP in adult patients with OAG or OHT who are insufficiently responsive to topical monotherapy with beta-blockers or PGAs and require a combination therapy, and who would benefit from PF eye drops
Route of administration [1]	Topical eye drop
Posology [1]	One eye drop in the conjunctival sac of the affected eye(s) once daily
Constituent agents [1]	Tafluprost 15 μg; timolol maleate 5 mg
Mechanism of action [1]	Tafluprost selectively acts via the human prostanoid FP receptor to reduce IOP by increasing the uveoscleral outflow of aqueous humor Timolol maleate is believed to nonselectively block beta-adrenergic receptors the ciliary epithelium to reduce aqueous humor production
Pivotal clinical studies(PF tafluprost/timolol FC vs. component agents) [18,19]	A 6-month study comparing efficacy, safety, and tolerability of the PF tafluprost/timolol FC vs. each of its individual PF components.[Pfeiffer et al. Adv Ther. 2014;31(12):1228–1246] Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% versus concomitant use of the ingredients. [Holló et al. J Ocul Pharmacol Ther. 2014;30(6):468–75]
Key real-world studies(PF tafluprost/timolol FC vs. baseline therapies) [20,22,31]	Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: the VISIONARY study. [Oddone et al. Adv Ther. 2020;37(4):1436–1451] Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: results of an open-label observational study.[Pillunat et al. Clin Ophthalmol. 2017;11:1051–1064] Switching to preservative-free tafluprost/timolol fixed-dose combination in the treatment of open-angle glaucoma or ocular hypertension: subanalysis of data from the VISIONARY study according to baseline monotherapy treatment. [Oddone et al. Adv Ther. 2022;39:3501–3521]

FC, fixed-dose combination; IOP, intraocular pressure; OHT, ocular hypertension; OAG, open-angle glaucoma; PF, preservative-free; PGA, prostaglandin analog.

2. Mechanism of action (including PK/PD)

The active constituents of the PF tafluprost/timolol FC act via independent complementary mechanisms, and the combined effect results in an additional IOP reduction compared to either compound alone [1,18]. Timolol is a nonselective beta-adrenergic receptor blocker that has been used as first-line therapy in the treatment of glaucoma since the 1970s [32–44]. The exact mechanism of action is yet to be established. However, it is believed to act via the beta receptors in the ciliary epithelium to reduce aqueous humor production and consequently lower IOP [40,43]. Tafluprost was the first PF PGA therapy to be approved by the US Food and Drug Administration for the treatment of OAG and OHT [45–55]. It is believed to act to increase uveoscleral aqueous humor outflow and lower IOP via its specific and potent affinity for the prostanoid FP receptor [55,56]. Studies indicate that tafluprost may increase blood flow rate in the optic nerve head [32,54].

Pharmacokinetic (PK) studies have shown that, post-administration at the ocular surface, tafluprost plasma concentrations peak at 10 minutes and decline below the lower limit of detection before 30 minutes [1]. Timolol plasma concentrations peak at 15 minutes and 37.5 minutes when dosed on days 1 and 8, respectively [1]. Studies indicate that the C_max and area under the curve (AUC) is lower for both tafluprost and timolol when dosed as an FC treatment, compared with dosing of the individual constituents [1]. The cytochrome P450 (CYP450) enzyme system is not involved in the metabolism of tafluprost. Overall, 27–38% of the tafluprost dose is excreted via the liver and approximately 44–58% in the feces [1]. Timolol is metabolized in the liver, primarily by the enzyme CYP2D6, with the resulting inactive metabolites mainly excreted through the kidneys [1].

3. Clinical applications (key efficacy data)

As single agents, both tafluprost and timolol have been proven to provide significant IOP reductions in people with OAG or OHT in RCTs and observational studies. Twice daily topical timolol therapy has shown significant IOP-lowering efficacy among patients with glaucoma, and a 5-year study indicated that treatment was associated with the prevention/delay of glaucomatous visual field loss [32–44]. PF tafluprost has demonstrated significant IOP reductions in treatment-naïve OAG and OHT patients and non-inferiority when compared with latanoprost monotherapy [45–52,57].

The PF tafluprost/timolol FC has demonstrated IOP-lowering efficacy that was superior when compared against each individual component and was comparable to the efficacy of concomitantly administered tafluprost and timolol therapies [18,19]. Table 1 summarizes IOP-lowering efficacy outcomes from key RCTs and real-world studies examining the PF tafluprost/timolol FC [18–20,22,31].

Table 1. Efficacy data from clinical trials and real-world studies.

Study	Population size	Design	Prior treatment	Mean baseline IOP, mmHg	Primary efficacy endpoint	Efficacy outcomes (mean IOP reduction)
Randomized controlled trials
Pfeiffer et al. 2014 [18]	n = 564	A 6-month, stratified, double-masked, randomized, multinational, multicenter study (60 centers across 10 countries)	PGA monotherapy or timolol monotherapy	Timolol users: ≥22 PGA users: ≥20	Change from baseline in the average diurnal IOP at Month 3 vs. PF tafluprost 0.0015% (once daily) or PF timolol 0.5% FC (twice) daily	Prior PGA users: 8.61 mmHg (33%) Prior timolol users: 8.55 mmHg (32%) Mean difference vs. prior PGA: 1.516 mmHg (p < 0.001) Mean difference vs. prior PGA: 0.885 mmHg (p = 0.044)
Holló et al. 2014 [19]	n = 400	A 6-month, prospective, double-masked, randomized, active-controlled, multicenter study (35 centers across 7 countries)	Treatment-naive, PGA, miotics, CAIs, α-adrenergic agonists, beta-adrenergic agonists	24.2–26.1	Change from baseline in mean diurnal IOP at Month 6 vs. concomitant PF tafluprost 0.0015% (once daily) + PF timolol 0.5% FC (twice) daily (NFC)	PF tafluprost/timolol FC: 8.0 mmHg (31.9%) NFC: 8.3 mmHg (33.1%) Mean treatment difference at Month 6 PF tafluprost/timolol FC vs. NFC: 0.241 mmHg
Real-world studies
Oddone et al. 2020 [22]	n = 577	A 6-month, observational, multicenter, European, prospective study (66 centers across 12 countries)	PGA monotherapy or β-blocker monotherapy	21.55	Mean absolute IOP change from baseline at Month 6	5.7 mmHg (24.9%; p < 0.0001)
Pillunat et al. 2018 [20]	n = 1,157	A 16-week, observational, multicenter, prospective open-label study (311 centers in Germany)	Monotherapy, FCs, multiple therapies and nonfixed combinations	21.4	Mean change from baseline at final study visit	4.9 mmHg (22.9%; p < 0.001)
Oddone et al. 2022 [31]	n = 577	Subanalysis of data according to baseline monotherapy for the VISIONARY study: a 6-month, observational, multicenter, European, prospective study (66 centers across 12 countries)	PGA monotherapy: Preserved latanoprost PF-latanoprost Tafluprost Bimatoprost Travoprost or β-blocker monotherapy	All PGA users: 21.4 Preserved latanoprost users: 22.4 PF-latanoprost users: 22.1 Tafluprost users: 20.8 Bimatoprost users: 20.6 Travoprost users: 20.0 Beta-blocker users: 21.9	Mean absolute IOP change from baseline at Month 6, according to baseline monotherapy	All PGA users: 5.4 mmHg (23.6%; p < 0.0001) Preserved latanoprost users: 6.3 mmHg (26.3%; p < 0.001) PF-latanoprost users: 5.6 mmHg (24.6%; p < 0.001) Tafluprost users: 4.9 mmHg (22.7%; p < 0.0001) Bimatoprost users: 4.6 mmHg (20.5%; p < 0.0001) Travoprost users: 4.7 mmHg (21.3%; p < 0.0001) Beta-blocker users: 6.6 mmHg (28.5%; p < 0.0001)

CAIs, carbonic anhydrase inhibitors; FAS, full analysis set; FC, fixed-dose combination; IOP, intraocular pressure; OHT, ocular hypertension; NFC, non-fixed combination; OAG, open-angle glaucoma; PF, preservative-free; PGA, prostaglandin analog.

3.1. Randomized controlled trials: efficacy data

Phase 3 RCT data demonstrated superior IOP-lowering efficacy with PF tafluprost/timolol FC compared with its constituent agents [18,19]. Pfeiffer et al. (2014) showed superiority with PF tafluprost/timolol FC therapy versus PF timolol monotherapy (p = 0.044) and PF tafluprost monotherapy (p < 0.001) [18]. In the tafluprost stratum, PF tafluprost/timolol FC reduced IOP from baseline by 8.2–9.0 mmHg compared with 6.8–7.4 mmHg with tafluprost [18]. PF tafluprost/timolol FC treatment provided IOP reductions of 7.1–9.0 mmHg (within group p < 0.001) at all time points in the timolol stratum. In comparison, timolol provided IOP reductions of 6.5–8.1 mmHg [18].

Holló et al. (2014) showed IOP-lowering efficacy with PF tafluprost/timolol FC therapy was comparable to that of the PF tafluprost and timolol non-fixed combination (NFC) [19]. Mean diurnal IOP reduction at 6-months was approximately 8.0 mmHg (31.9%) with PF tafluprost/timolol FC therapy and 8.3 mmHg (33.1%) with concomitantly administered tafluprost and timolol [19].

3.2. Real-world studies in the clinical practice setting: efficacy data

Real-world data from the VISIONARY study (2020) and Pillunat et al. (2017) revealed that a switch to the PF tafluprost/timolol FC was associated with significant and clinically meaningful IOP reductions, regardless of the prior therapy used [20,22].

The VISIONARY study (a 6-month, observational, multicenter study conducted at 66 ophthalmology clinics across Europe), showed that a switch to PF tafluprost/timolol FC therapy from PGA or beta-blocker monotherapy resulted in significant IOP reductions in routine clinical practice (p < 0.0001) [22]. IOP was lowered from baseline to ≤16 mmHg, and reductions of >20% were observed from Week 4 that were maintained over the 6-month study period [22]. Mean IOP reduction from baseline at Month 6 was 5.7 mmHg (24.9%) [22]. Subgroup analysis revealed that prior beta-blocker users achieved the greatest IOP reductions at Month 6 (6.6 mmHg; 28.5%; p < 0.0001), while PGA monotherapy users achieved Month 6 IOP reductions of 5.4 mmHg (23.6%; p < 0.0001) [22]. Those using preserved latanoprost at baseline exhibited the greatest IOP reductions at Month 6 among prior PGA monotherapy users (6.3 mmHg; 26.3%; p < 0.001) [31]. IOP reduction in other PGA user subgroups ranged from 4.6 mmHg (20.5%) in those previously using bimatoprost to 5.6 mmHg (24.6%) in prior PF-latanoprost users (p < 0.001 for all prior PGA user subgroups) [31].

An observational study of 1,075 OAG/OHT patients in Germany showed that mean IOP was reduced by 4.9 mmHg, from 21.4 mmHg at baseline to 16.5 mmHg (p < 0.001) after switching to PF tafluprost/timolol FC therapy from any prior monotherapy, FC therapy or NFC (efficacy assessed post-switch at 4–16 weeks) [20]. At final study visits, those previously using a topical PGA, beta-blocker, carbonic anhydrase inhibitors (CAI), or α2-agonist monotherapy demonstrated respective IOP reductions of 4.7 mmHg (22.3%; p < 0.001), 5.7 mmHg (25.4%; p < 0.001), 5.2 mmHg (25.0%; p < 0.001), and 6.4 mmHg (27.6%; p < 0.001) from baseline [20]. Among baseline users of PGA/beta-blocker FC, CAIs/beta-blocker FC, and other FC therapies, mean IOP was reduced by 12.7% (p < 0.001), 19.3% (p < 0.001), and 26.7% (p = 0.007), respectively [20]. Patients treated with NFCs at baseline showed similar IOP reductions to those of patients treated with FC formulations of the same drug types at baseline [20].

4. Safety and tolerability evaluation

The absence of preservative agents in the PF tafluprost/timolol FC supports improvements in tolerability that are likely to result in better adherence and treatment compliance [58]. Table 2 presents an overview of the safety and tolerability outcomes from key RCTs and real-world studies examining the use of PF tafluprost/timolol FC in glaucoma [18–20,22,31].

Table 2. Safety and tolerability data from clinical trials and real-world studies.

Study	Key reported improvements in ocular signs from baseline	Key reported improvements in subjective symptoms from baseline	Reported AEs with PF tafluprost/timolol FC treatment, n (%)
Randomized clinical trials
Pfeiffer et al. 2014 (n = 564) [18]	N/A	N/A	PF tafluprost/timolol FC vs. Timolol subgroup (n = 95): Conjunctival hyperemia: 4 (4.2) Dry eye: 2 (2.1) Eye irritation:2 (2.1) Eye pain: 2 (2.1) Eye pruritus: 4 (4.2) Foreign body sensation: 3 (3.2) Ocular discomfort: 2 (2.1) Ocular hyperemia: 5 (5.3) Vision blurred: 2 (2.1)	PF tafluprost/timolol FC vs. tafluprost subgroup (n = 188): Conjunctival hyperemia: 5 (2.7) Eye irritation:5 (2.7) Eye pain: 7 (3.7) Eye pruritus: 6 (3.2) Foreign body sensation: 3 (1.6) Ocular hyperemia: 4 (2.1) Vision blurred: 3 (1.6) Eyelid erythema: 1 (0.5) Eyelash growth: 2 (1.1) Eyelash discoloration:1 (0.5) Eyelash thickening:1 (0.5) Photophobia:1 (0.5)
Holló et al. 2014 (n = 400) [19]	Conjunctival hyperemia showed decreasing tendency over the course of the study	N/A	Ocular AEs: Conjunctival hyperemia:13 (6.5) Growth of eyelashes: 5 (2.5) Eyelash thickening:5 (2.5) Eyelash discoloration: 5 (2.5) Photophobia: 3 (1.5) Eye irritation: 4 (2.0) Eye pain: 4 (2.0) Eye pruritus: 3 (1.5) Dry eye:1 (0.5) Foreign body sensation: 2 (1.0) Ocular hyperemia: 3 (1.5)	Non-ocular adverse events: Headache: 1 (0.5) Urticaria: 1 (0.5)
Real-world studies
Oddone et al. 2020 (n = 577) [22]	CFS score: 32.7% demonstrated a reduction (p < 0.0001) Conjunctival hyperemia: 38.7% demonstrated a reduction (p < 0.0001)	Dry eye (p < 0.001) Irritation (p < 0.001) Itching (p < 0.001) Foreign body sensation (p < 0.001) Eye pain (p = 0.058)	Treatment-related ocular AEs: Blepharal pigmentation: 2 (0.3) Blepharitis: 1 (0.2) Conjunctival hyperemia: 1 (0.2) Ocular hyperemia: 4 (0.7) Conjunctivitis: 2 (0.3) Eye pain: 23 (4.0) Eyelid erythema: 1 (0.2) Eyelid edema: 1 (0.2) Eye Pruritis: 2 (0.3) Dry eye: 1 (0.2) Keratitis: 2 (0.3) Foreign body sensation: 2 (0.3) Eyelash growth: 1 (0.2) Blurred vision: 1 (0.2) Eye discharge: 1 (0.2) Ocular irritation: 1 (0.2) Iris hyperpigmentation: 1 (0.2) Lacrimation increased: 1 (0.2) Ocular discomfort: 2 (0.3)	Treatment-related other AEs: Respiratory Asthma: 1 (0.2) Status asthmaticus: 1 (0.2) Neurological Headache: 1 (0.2) Dizziness: 3 (0.5) Cardiovascular Palpitations: 1 (0.2) Atrioventricular block: 1 (0.2) Bradycardia: 1 (0.2) Dermatological Skin hyperpigmentation: 1 (0.2) Abnormal hair growth: 1 (0.2) Rash: 1 (0.2) Immune disorders Hypersensitivity/allergy: 4 (0.7) General disorders Fatigue: 2 (0.3) Chest pain: 1 (0.2)
Pillunat et al. 2018 (n = 1,157) [20]	CFS score: reduction in score (p < 0.01) Conjunctival hyperemia: reduction in severity (p < 0.001) LIPCOF severity: reduction in grading (p < 0.001)	Dry eye (p < 0.001) Irritation (p < 0.001) Itching (p < 0.001) Foreign body sensation (p < 0.001) Eye pain (p < 0.001)	Ocular AEs: Hyperemia: 3 (0.3) Hyperemia/chemosis: 1 (0.1) Hyperemia/foreign body sensation: 1 (0.1) Hyperemia/eye pain: 1 (0.1) Hyperemia, dry eye sensation: 1 (0.1) Hyperemia/allergy: 1 (0.1) Hyperemia/irritation: 1 (0.1) Blepharitis: 1 (0.1) Burning: 6 (0.5) Burning/itching: 2 (0.2) Burning/stinging: 1 (0.1) Blurred vision/irritation:1 (0.1) Dry eye sensation: 1 (0.1) Dry eye sensation/itching: 1 (0.1) Dry eye sensation/tired eyes: 1 (0.1) Eye pain/irritation: 1 (0.1) Foreign body sensation: 1 (0.1) Irritation: 3 (0.3) Tearing/blurred vision: 1 (0.1)	Systemic and local: Asthmatic disease: 1 (0.1) Coughing/breathing issues/irritation: 1 (0.1) β-blocker contraindication: 1 (0.1) Hair loss: 1 (0.1) Hypertonia: 1 (0.1) Vertigo: 1 (0.1) Vertigo/palpitation: 1 (0.1)
Oddone et al. 2020 (n = 577) [31]	CFS score: significantly reduced in baseline PGA users (p = 0.0001) – mainly driven by the CFS change among prior bimatoprost users (p = 0.0013). Conjunctival hyperemia: reduction in severity among all prior PGA users (p < 0.0001). Conjunctival hyperemia: reduction in severity among prior preserved latanoprost users (p < 0.001).	N/A	All treatment-related AEs were reported in the primary manuscript (Oddone et al. 2020 [22]). Safety data were not examined in the subanalysis according to baseline monotherapy.

AEs, adverse events; CFS, corneal fluorescein staining; FC, fixed-dose combination; LIPCOF, lid-parallel conjunctival folds; N/A, not available; PF, preservative-free; PGA, prostaglandin analog.

The addition of timolol has been shown to enhance the tolerability of PGA agents in FC therapies [35]. Timolol is associated with few topical side effects, although it has some important systemic adverse effects on the cardiac and respiratory systems [40,41,59,60]. It is associated with symptomatic bradycardia and bronchospasms [40,41,59,60]. Timolol-containing FC glaucoma medications are therefore contraindicated in people with sinus bradycardia, sick sinus syndrome, including sinoatrial block, second- or third-degree atrioventricular block not controlled with pacemaker, overt cardiac failure, and cardiogenic shock [1]. People with reactive airway disease, including current bronchial asthma, history of bronchial asthma, or severe chronic obstructive pulmonary disease, should not be prescribed a timolol-containing therapy [1]. Individuals with cardiac disorders (e.g. coronary heart disease and cardiac failure) and hypotension should be critically assessed and monitored for deterioration or adverse events (AEs) when treated with timolol-containing therapies/regimens [1]. In addition, beta-blockers such as timolol may mask the signs and symptoms of acute hypoglycemia and should be used with caution in individuals with labile diabetes [1]. Tafluprost and other PGAs may be associated with peri-orbitopathy, including eyelash growth, darkening of the eyelid skin, and increased iris pigmentation [1]. Some of these changes may be permanent and can lead to differences in appearance between the eyes when only one eye is treated [1].

4.1. Safety and tolerability in clinical studies

Data from RCTs with PF tafluprost/timolol FC therapy showed that AEs were typically reported at the site of administration with conjunctival and ocular hyperemia being the most common [18,19]. However, Phase 3 studies reported that 70–80% of patients reported no discomfort upon instillation of PF tafluprost/timolol FC, and safety and tolerability outcomes were comparable to the NFC comprising the constituent therapies [18,19]. Incidence of conjunctival hyperemia tended to decrease over time, after peaking at Week 2, with either PF tafluprost/timolol FC or the constituent NFC [19].

4.2. Safety and tolerability in real-world studies

Corneal fluorescein staining (CFS; Oxford Grade Scale 0–V), an indicator of OSD severity, was significantly reduced from baseline at Month 6 (p < 0.0001) in VISIONARY study participants [22]. Mean CFS score was reduced by almost 30%, and conjunctival hyperemia was also significantly reduced from baseline at Month 6 (p ≤ 0.029) [22]. Subgroup analysis revealed that conjunctival hyperemia was significantly reduced in patients switching from preserved latanoprost but not in those previously using PF latanoprost, suggesting that the presence of preservative at baseline was associated with a higher starting severity of conjunctival hyperemia and therefore a more profound improvement was observed post-switch [31]. The greatest improvements in CFS score among prior PGA users were among baseline bimatoprost users [31]. Other switch studies and systematic reviews have also suggested that tolerability improvements can accompany a change to PF tafluprost/timolol FC therapy from bimatoprost-containing treatments [21,28]. Most participants (>80%) did not report AEs, and those reported were typically mild (93%) in severity and resolved/resolving by data cutoff (71.3%) [22]. In total, 69 treatment-related AEs were reported, of which 45 were ocular disorders [22]. One serious treatment-related AE was reported (status asthmaticus) and may have been due to off-label prescribing as PF tafluprost/timolol FC is contraindicated for use in people with bronchial asthma [1,22].

Pillunat et al. (2014) showed reductions in conjunctival hyperemia severity following a switch to PF tafluprost/timolol FC, irrespective of the treatment used at baseline [20]. Changes in conjunctival staining were statistically significant (p < 0.01) in all prior PGA users and those previously using PGA/timolol FC therapies (p < 0.01) [20]. Lid-parallel conjunctival folds (LIPCOF) were significantly decreased after a change to PF tafluprost/timolol FC therapy among prior PGA (p < 0.001) and PGA/timolol users (p < 0.01) [20]. The frequency and severity of ocular symptoms were reduced significantly compared to baseline (p < 0.001) [20]. Treatment was terminated by 25 patients (2.2%) due to lack of efficacy, 29 patients (2.5%) because of local tolerability issues and 7 (0.6%) stopped their treatment as a result of systemic intolerance [20].

4.3. Safety in special populations

Data are limited regarding the use of PF tafluprost/timolol FC in pregnant women, and the use of effective contraception is recommended during PF tafluprost/timolol FC treatment for women of childbearing potential [1]. PF tafluprost/timolol FC should not be used during pregnancy unless clearly necessary when no other treatment options are available [1]. Beta-blockers are excreted in breast milk, but the timolol dose used in eye drops is unlikely to be sufficient to produce clinical symptoms of beta-blockade in the infant [1]. PF tafluprost/timolol FC should be used with caution in people with hepatic or renal impairment as the constituents of this treatment have not been studied in these populations [1]. No dosage alteration is required in elderly patients [1].

4.4. Comparison with safety and tolerability of other drugs

Hollo et al. (2014) compared RCT treatment outcomes with PF tafluprost/timolol FC against other FC therapies and showed fewer superficial ocular side effects and less conjunctival hyperemia compared with bimatoprost/timolol FC or travoprost/timolol FC [30]. Real-world data examining efficacy and tolerability with PF tafluprost/timolol FC treatment in patients with OAG following a switch from preserved or PF bimatoprost/timolol FC showed that IOP-lowering efficacy was maintained, while signs and symptoms of OSD were improved post-switch [21]. This suggests that tolerability issues may also be associated with the constituent agents themselves as well as preservatives/BAK [21].

5. Conclusion

RCT and real-world data collected to date demonstrate that PF tafluprost/timolol FC therapy provides significant and clinically meaningful IOP-lowering efficacy in people with OAG/OHT. The safety and tolerability profile of PF tafluprost/timolol FC indicates that the therapy may be better tolerated compared with preservative-containing topical medications or other PGA-based treatments associated with potential tolerability issues. This may result in enhanced adherence and contribute to the additional IOP-lowering efficacy seen following a treatment switch.

6. Expert opinion

PF tafluprost/timolol FC is a powerful IOP-lowering treatment that is well tolerated and has a good safety profile [18–31,,61]. Analysis of RCT data demonstrates that PF tafluprost/timolol FC is associated with fewer local side effects compared with some other PGA/timolol therapies [18,19,30]. Real-world studies also show that improvements in ocular tolerability following a switch to PF tafluprost/timolol FC (from a range of other treatment types and formulations) can be accompanied by additional IOP reductions [20–22]. Improved IOP-lowering efficacy might, in part, be due to enhanced treatment adherence as a consequence of more acceptable tolerability with a PF topical therapy [22,31]. As with many long-term conditions, compliance with treatment regimens represents a major ongoing challenge for clinicians. Patients are generally not able to feel the benefit that they are gaining from their regular medications and can forget to use their eye drops or they may not understand the importance of instilling their glaucoma medications regularly, as prescribed by their ophthalmologist. However, adherence and persistence with treatment is critical in achieving long-term IOP control to slow the progression of glaucoma and preserve the patient’s eyesight [2,3]. A further benefit for health-care systems also exists with improved treatment adherence and tolerability because medicine wastage and resource usage will be reduced as a result of patients using their medicines optimally and requiring fewer clinical appointments to address issues associated with poor efficacy or side-effects.

As topical medications are important first- and second-line treatments for glaucoma and given the impact of the disease on vision-related QoL, prescribing must consider the impact of treatment tolerability from the patient’s perspective and the likelihood of maintaining long-term usage [2,12–16]. This is illustrated through the outcomes from the VISIONARY study, which reflected real-world clinical practice regarding direct treatment switches from PGA/beta-blocker monotherapy to FC therapy [22,31]. The study showed that ocular symptoms and conjunctival hyperemia were significantly reduced in severity following a switch to PF tafluprost/timolol FC, and investigators reported improved patient compliance with PF tafluprost/timolol FC therapy versus prior monotherapy [22]. Prior preserved latanoprost users benefitted more from the switch to PF tafluprost/timolol FC therapy in terms of improvements in conjunctival hyperemia severity and also showed the greatest reduction in IOP compared with the other PGA monotherapy subgroups [31]. Patients who show signs of tolerability issues and poor IOP control with their initial PGA monotherapies may benefit from a step up to PF tafluprost/timolol FC to address both aspects of their treatment [20–22,30].

The currently available evidence highlights the need for more individualized approaches to OAG/OHT treatment that consider tolerability and factors influencing patient adherence [2,11,61]. Personalized approaches to treatment with topical medications, particularly utilizing the available PF FC formulations, will be critical if we are to improve glaucoma care. Tailored treatment pathways should enable IOP control to be achieved at an early stage in the disease pathway so that vision may be preserved for longer, delaying the need for more invasive/surgical interventions. A recently published series of OAG and OHT patient cases illustrates this point [61]. Patients who were switched to PF tafluprost/timolol FC from either maximal topical therapy or initial monotherapy had improved IOP control and told their clinician that their adherence was better due to enhanced tolerability and less pain/discomfort upon administration compared with prior treatment(s) [61]. The cases also revealed reduced corneal staining in the anterior segment and a marked reduction in inflammatory cells at the surface of the eye (shown via confocal microscopy) following a switch to PF tafluprost/timolol FC from maximal therapy [61]. These cases support a ‘less is more’ approach to glaucoma therapy and emphasize the need for holistic management of ocular health alongside IOP reduction. All too often, clinicians may be tempted to escalate treatment to include multiple therapies with the goal of maximizing IOP lowering, even at the cost of tolerability. Clinicians should not underestimate the importance of picking up on non-verbal cues and discussing potential tolerability issues with their patients in order to identify associated adherence issues and optimize treatment [61]. People with glaucoma are vulnerable to OSD, and evidence suggests that better tolerated treatments might support improvements in outcomes as well as enhanced QoL [11–16,61,62]. In addition, it is widely accepted now that chronic use of preserved topical therapies negatively affects future surgical outcomes, and this should be a consideration for clinicians during earlier stages of disease management [10].

Generally, there is a lack of consistency regarding study design across many real-world investigations of topical glaucoma therapies, and the VISIONARY study was the first to specifically examine efficacy and tolerability outcomes following a step up to FC treatment from topical PGA/beta-blocker monotherapy, in line with European guidelines. Ophthalmologists would benefit from further data in this area to inform and support confident decision-making in their daily clinical practice. Future studies should examine the impact of tolerability issues and OSD associated with topical FC therapies to better understand the implications for long-term treatment, IOP reduction, slowing of disease progression and eventual sight loss.

Declaration of interest

F Oddone has received consultancy fees from Santen, Allergan, Sooft, Omikron Italia and Centervue. and Novartis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Scientific accuracy review

Santen provided a scientific accuracy review at the request of the journal editor.

Author contribution statement

Francesco Oddone was responsible for the conceptualization, development and critical review of content included in this manuscript.

Authorship

Dr Francesco Oddone has developed this review article at the invitation of the Editorial team at Expert Opinion on Drug Safety. Dr Oddone takes responsibility for the integrity of the work as a whole and has given final approval for the version to be published.

Consent

This article is based upon previously conducted studies and does not involve any new studies of human or animal subjects. The author was involved in some of the studies discussed within the paper that included human subjects, all of which complied with the tenets of the Declaration of Helsinki of 1964 and subsequent revisions and used protocols that had been approved by relevant Institutional Review Boards/Ethics Committees and included patients who had provided written informed consent.

Data availability statement

This paper presents a review of previously published data from numerous sources. Therefore, please refer to the original publications for details of data availability for individual studies (https://pubmed.ncbi.nlm.nih.gov).

Additional information

Funding

Publication support fees and article publishing charges were kindly provided by Santen SA, Switzerland. The Italian Ministry of Health and Fondazione Roma supported the creation of this review article. Medical writing services were provided on behalf of the author by Rebecca Down at Copperfox Communications Limited.