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

Figures & data

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.

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.

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.

Santen UK. Taptiqom 15 micrograms/ml + 5 mg/ml eye drops, solution in single-dose container Summary of product characteristics . 2021. [cited 2021 Feb 15]. Available from: https://medicines.org.uk/emc/product/6917

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Pfeiffer N, Traverso CE, Lorenz K, et al., A 6-month study comparing efficacy, safety, and tolerability of the preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% versus each of its individual preservative-free components. Adv Ther. 2014;31(31): 1228–1246.

 PubMedGoogle Scholar

Holló G, Hommer A, Antón López A, et al., Efficacy, safety, and tolerability of preservative-free fixed combination of tafluprost 0.0015%/timolol 0.5% versus concomitant use of the ingredients. J Ocul Pharmacol Ther. 2014;30(6): 468–475.

 PubMed Web of Science ®Google Scholar

Pillunat LE, Erb C, Ropo A, et al. 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. Clin Ophthalmol. 2017;11:1051–1064.

 PubMed Web of Science ®Google Scholar

Oddone F, Tanga L, Kóthy P, et al., Treatment of open-angle glaucoma and ocular hypertension with preservative-free tafluprost/timolol fixed-dose combination therapy: the VISIONARY study. Adv Ther.2020; 37(37): 1436–1451.

 PubMedGoogle Scholar

Oddone F, Kirwan J, Lopez-Lopez F, et al., 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. Adv Ther.2022; 39(8): 3501–3521.

 PubMed Web of Science ®Google Scholar

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).