Product Monograph - Saflutan
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TABLE OF CONTENTS
PART I: HEALTH PROFESSIONAL INFORMATION ................................................................. 3
1 INDICATIONS ................................................................................................................. 3
1.1 Pediatrics ............................................................................................................. 3 1.2 Geriatrics ............................................................................................................. 3
2 CONTRAINDICATIONS .................................................................................................. 3
3 DOSAGE AND ADMINISTRATION ................................................................................ 3
3.1 Recommended Dose and Dosage Adjustment ..................................................... 3 3.2 Administration ...................................................................................................... 3 3.3 Missed Dose ........................................................................................................ 4
4 OVERDOSAGE ............................................................................................................... 4
5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING ......................... 4
6 WARNINGS AND PRECAUTIONS ................................................................................. 5
6.1 Special Populations ............................................................................................. 6 6.1.1 Pregnant Women ................................................................................................ 6 6.1.2 Breast-feeding .................................................................................................... 7 6.1.3 Pediatrics ............................................................................................................ 7 6.1.4 Geriatrics ............................................................................................................ 7
7 ADVERSE REACTIONS ................................................................................................. 7
7.1 Adverse Reaction Overview ................................................................................. 7 7.2 Clinical Trial Adverse Reactions ........................................................................... 8 7.3 Less Common Clinical Trial Adverse Reactions (<1%) ........................................ 9 7.4 Post-Market Adverse Reactions ........................................................................... 9
8 DRUG INTERACTIONS ................................................................................................ 10
8.1 Overview ............................................................................................................ 10 8.2 Drug-Drug Interactions ....................................................................................... 10 8.3 Drug-Food Interactions ...................................................................................... 10 8.4 Drug-Herb Interactions ....................................................................................... 10 8.5 Drug-Laboratory Test Interactions ...................................................................... 10
9 ACTION AND CLINICAL PHARMACOLOGY ............................................................... 10
9.1 Mechanism of Action .......................................................................................... 10 9.2 Pharmacodynamics ........................................................................................... 11 9.3 Pharmacokinetics ............................................................................................... 11
10 STORAGE, STABILITY AND DISPOSAL ..................................................................... 12
PART II: SCIENTIFIC INFORMATION ..................................................................................... 13
11 PHARMACEUTICAL INFORMATION ........................................................................... 13
12 CLINICAL TRIALS ........................................................................................................ 13
12.1 Trial Design and Study Demographics ............................................................... 13 12.2 Study Results ..................................................................................................... 15
13 NON-CLINICAL TOXICOLOGY .................................................................................... 21
PATIENT MEDICATION INFORMATION ................................................................................. 23
PART I: HEALTH PROFESSIONAL INFORMATION
1 INDICATIONS
SAFLUTAN™ (tafluprost ophthalmic solution, 15 mcg/mL) is indicated for:
- the reduction of elevated intraocular pressure in patients with open-angle glaucoma or ocular hypertension.
1.1 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
1.2 Geriatrics
Geriatrics (>65 years of age): No overall clinical differences in efficacy or adverse events profile have been observed between elderly (> 65 years) and non-elderly (≤ 65 years) patients.
2 CONTRAINDICATIONS
Tafluprost is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.
3 DOSAGE AND ADMINISTRATION
3.1 Recommended Dose and Dosage Adjustment
Pediatrics (< 18 years of age): Health Canada has not authorized an indication for pediatric use.
Adults (>18 years of age): The recommended dose is one drop of SAFLUTAN in the conjunctival sac of the affected eye(s) once daily in the evening.
The dose should not exceed once daily as more frequent administration of prostaglandin analogues may lessen the intraocular pressure lowering effect and increase the frequency and severity of adverse events.
Reduction of the intraocular pressure starts approximately 2 to 4 hours after the first administration with the maximum effect reached after 12 hours.
Geriatrics (> 65 years of age): No dosage adjustment is required for elderly patients.
3.2 Administration
SAFLUTAN is a sterile solution that does not contain a preservative. For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.
SAFLUTAN may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug product is being used, each one should be administered at least 5 minutes apart.
To reduce the risk of darkening of the eyelid skin patients should blot off any excess solution from the skin. As with any other eye drops, nasolacrimal occlusion or gently closing the eyelid after administration is recommended. This may reduce the systemic absorption of products administered via the ocular route.
Contact lenses should be removed prior to the administration of SAFLUTAN, and may be reinserted 15 minutes following administration.
The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded immediately after administration.
3.3 Missed Dose
If a dose is missed at its usual time, a single drop should be used as soon as possible, and then the next dose should be administered at the usual time. A double dose should not be given.
4 OVERDOSAGE
No case of overdose has been reported. Overdose is unlikely to occur after ocular administration. If overdose with SAFLUTAN (tafluprost ophthalmic solution, 15 mcg/mL), occurs, treatment should be symptomatic.
5 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING
Table 1 – Dosage Forms, Strengths, Composition and Packaging.
Dosage Form
SAFLUTAN (tafluprost ophthalmic solution, 15 mcg/mL) is supplied as a sterile solution in single–dose containers. One single-dose container (0.3 mL solution) contains 4.5 mcg of tafluprost. Ten single-dose (2 strips of 5 each) individual unit dose pipettes are provided in one foil pouch. There are 30 pipettes per carton.
For management of a suspected drug overdose, particularly an accidental oral ingestion, contact your regional Poison Control Centre.
| Route of Administration | Dosage Form / Strength/Composition | Non-medicinal Ingredients |
| Ophthalmic | Solution, each mL contains 15 mcg tafluprost | disodium edetate, glycerol, polysorbate 80, sodium dihydrogen phosphate dihydrate, and hydrochloric acid and/or sodium hydroxide. |
Composition
SAFLUTAN (tafluprost ophthalmic solution, 15 mcg/mL) is a clear, colorless, buffered, sterile solution with a pH range of 5.5 - 6.7 and an Osmolality range of 260 - 300 mOsmol/kg.
6 WARNINGS AND PRECAUTIONS
General
Tafluprost ophthalmic solution (15 mcg/mL) has been reported to cause changes to pigmented tissues. The most frequently reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation. Some of these changes may be permanent, and may lead to differences in appearance between the eyes when only one eye is treated (See ADVERSE REACTIONS).
Carcinogenesis and Mutagenesis
See Toxicology.
Driving and Operating Machinery
As with any ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machinery.
Contact lenses should be removed prior to the administration of SAFLUTAN, and may be reinserted 15 minutes following administration.
Hepatic
Hepatic Insufficiency
SAFLUTAN has not been studied in patients with hepatic insufficiency and should therefore be used with caution in such patients.
Ophthalmologic
Eyelash Changes
SAFLUTAN may gradually change eyelashes and vellus hair in the treated eye. These changes include increased length, color, thickness, pigmentation, the number of lashes or hairs, and misdirected growth of eyelashes (trichiasis). Eyelash changes are usually reversible upon discontinuation of treatment.
Eyelid Skin Darkening
Eyelid skin darkening has been reported in association with the use of SAFLUTAN. Studies with other prostaglandin analogues indicate that eyelid skin darkening is usually reversible upon discontinuation of treatment.
Patients who are expected to receive treatment in only one eye should be informed about the potential for increased brown pigmentation of the iris, periorbital tissue, and eyelashes in the treated eye and thus, heterochromia between the eyes. They should be advised of the potential for a disparity between the eyes in length, thickness, and/or number of eyelashes. These changes in pigmentation and eyelash growth may be permanent. The long term effects of increased pigmentation are not known.
Intraocular Inflammation
Caution is recommended in patients with known risk factors for iritis/uveitis and should generally not be used in patients with active intraocular inflammation.
Macular Edema
Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α analogues. These reports have mainly occurred in aphakic patients, pseudophakic patients with a torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for macular edema. Therefore, caution is recommended when using tafluprost in these patients.
Pigmentation
SAFLUTAN may gradually cause changes to pigmented tissues. Pigmentation is expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost, pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of increased pigmentation. The long term effects of increased pigmentation are not known.
The change in iris pigmentation occurs slowly and may not be noticeable for several months. The change in eye color has predominantly been seen in patients with mixed colored irises, e.g. blue-brown, grey-brown, yellow-brown and green-brown. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with SAFLUTAN can be continued in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly.
Renal
Renal Insufficiency
SAFLUTAN has not been studied in patients with renal insufficiency and should therefore be used with caution in such patients.
Respiratory
There is no experience with tafluprost in patients with severe or uncontrolled asthma. Such patients should therefore be treated with caution.
There is no experience with tafluprost in neovascular, angle-closure, narrow-angle or congenital glaucoma. There is only limited experience with tafluprost in aphakic patients and in pigmentary or pseudoexfoliative glaucoma.
Pulmonary Insufficiency
SAFLUTAN has not been systematically studied in patients with pulmonary insufficiency and should therefore be used with caution in such patients.
6.1 Special Populations
6.1.1 Pregnant Women
There are no adequate and well-controlled studies of tafluprost ophthalmic solution (15 mcg/mL) performed in pregnant women. Tafluprost-related effects were observed in embryo-fetal developmental studies in animals (see below). Although results from animal studies are not always predictive of human response, SAFLUTAN should not be used during pregnancy or by women attempting to become pregnant unless the potential benefit justifies the potential risk to the fetus.
Women of childbearing age/potential should have adequate contraceptive measures in place. In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343-times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during the critical period of development that were 5.3-times higher than the clinical exposure based on Cmax. At the no effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL).
In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offspring at tafluprost doses greater than 20-times the clinical dose. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison.
6.1.2 Breast-feeding
It is unknown whether SAFLUTAN or its metabolites are excreted in human milk. A study in lactating rats demonstrated that radiolabeled tafluprost and/or its metabolites (0.1% of the dose) were excreted in milk. Because many drugs are excreted in human milk, caution should be exercised when SAFLUTAN is administered to a nursing woman.
6.1.3 Pediatrics
Pediatrics (<18 years of age): No data are available to Health Canada; therefore, Health Canada has not authorized an indication for pediatric use.
6.1.4 Geriatrics
Geriatrics (>65 years of age): No overall clinical differences in efficacy or adverse events profile have been observed between elderly (> 65 years) and non-elderly (≤ 65 years) patients. Therefore, no dosage adjustment is required for elderly patients.
7 ADVERSE REACTIONS
7.1 Adverse Reaction Overview
Tafluprost has been studied in 905 patients in five randomized, double-masked, parallel group, multicenter, monotherapy, active-controlled studies, up to 24 months in duration, primarily using a preservative-containing formulation. The most commonly reported adverse reactions were similar in all studies. The most common drug-related adverse reaction in patients treated with tafluprost was conjunctival hyperemia, which was reported in 4 to 20% of patients. Most adverse reactions were mild. Adverse drug reactions led to discontinuation in 1.7% of patients participating in these studies.
7.2 Clinical Trial Adverse Reactions
Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.
The safety assessment of SAFLUTAN is based on the pooled safety data from five randomized clinical studies using tafluprost (administered once daily) and active comparators as controls (either latanoprost or timolol) in patients with primary open-angle glaucoma or ocular hypertension. The pooled safety data are a summation of all the adverse reactions for the total duration of each study (i.e., 4-week data for study 15-002, 6-week data for study 74457, 3-month data for study 001, 12-month data for study 15-003 and 24-month data for study 74458).
The following drug-related adverse reactions, as determined by the investigator, were reported at ≥ 1% in the overall population receiving the clinical dose of tafluprost during treatment from 4- weeks up to 24 months.
Table 2 - Number (%) of Patients with Tafluprost Drug-Relateda Adverse Events (≥ 1%) Protocols 15-002, 74457, 74458, 15-003 and 001
| Adverse Event | Tafluprost 0.0015% (Nb=905) nc (%) | Timolol Maleate 0.5% (Nb=543) nc (%) | Latanoprost 0.005% (Nb=311) nc (%) |
| Eye disorders | |||
| Conjunctival hyperemia | 28 (3.1) | 4 (0.7) | 6 (1.9) |
| Conjunctival redness | 12 (1.3) | 0 (0.0) | 2 (0.6) |
| Eye redness | 33 (3.6) | 12 (2.2) | 7 (2.3) |
| Ocular hyperemia | 17 (1.9) | 2 (0.4) | 2 (0.6) |
| Dry eye | 20 (2.2) | 7 (1.3) | 7 (2.3) |
| Eyelash darkening | 14 (1.5) | 0 (0.0) | 9 (2.9) |
| Foreign body sensation in eyes | 12 (1.3) | 5 (0.9) | 5 (1.6) |
| Growth of eyelashes | 21 (2.3) | 0 (0.0) | 11 (3.5) |
| Ocular pain | 25 (2.8) | 11 (2.0) | 6 (1.9) |
| Burning eyes | 29 (3.2) | 13 (2.4) | 12 (3.9) |
| Eye irritation | 11 (1.2) | 7 (1.3) | 4 (1.3) |
| Eyes stinging | 14 (1.5) | 10 (1.8) | 4 (1.3) |
| Ocular pruritus | 34 (3.8) | 9 (1.7) | 4 (1.3) |
| Photophobia | 14 (1.5) | 3 (0.6) | 2 (0.6) |
| Nervous system disorder | |||
| Headache | 14 (1.5) | 4 (0.7) | 3 (1.0) |
a. Determined by the investigator to be possibly, probably or definitely drug-related.
b. N = Number of patients in the treatment group.
c. n = Number of patients with the corresponding adverse event.
7.3 Less Common Clinical Trial Adverse Reactions (<1%)
Eye disorders:
Uncommon (≥1/1 000 to <1/100): abnormal sensation in eye, anterior chamber cell, anterior chamber flare, blepharal pigmentation, blepharitis, bloodshot eye, cataract, cataract cortical, cataract nuclear, chemosis, conjunctival disorder, conjunctival follicles, conjunctival pigmentation, deposit eye, epiphora, erythema of eyelid, eye ache, eye discharge, eyelash thickening, eyelid oedema, eyelids pruritus, eyes tearing, hyperaemia eyelid, iris hyperpigmentation, lacrimation, ocular discomfort, punctate keratitis, scotoma, superficial punctate keratitis, swollen eyelid, tired eyes, vision blurred, vision decreased, visual acuity reduced, visual field constriction, visual field defect, xerophthalmia
Very Rare (<1/10,000): Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas
Gastrointestinal disorders:
Uncommon (≥1/1 000 to <1/100): dry mouth
Respiratory, thoracic and mediastinal disorders:
Uncommon (≥1/1 000 to <1/100): cough, sore throat
Skin and subcutaneous tissue disorders:
Uncommon (≥1/1 000 to <1/100): darkened skin, hypertrichosis of the eyelid
Since the first market authorization, preservative-free tafluprost 0.0015% was evaluated in a twelve-week, randomized, double-masked, active-controlled clinical study (N=320), no new drug-related adverse reactions were reported (incidence ≥ 1%). The drug-related incidence of conjunctival hyperemia was 4.1%.
7.4 Post-Market Adverse Reactions
The following adverse reactions have been identified during post-approval use of SAFLUTAN.
Eye disorders: Allergic conjunctivitis, deepening of the eyelid sulcus, iritis/uveitis, corneal erosion, retinal detachment, conjunctivitis
Nervous system disorders: Dizziness
Respiratory, thoracic and mediastinal disorders: Exacerbation of asthma, dyspnea
Immune system disorders: Hypersensitivity reactions, including anaphylactic shock
8 DRUG INTERACTIONS
8.1 Overview
No drug-drug interactions are anticipated in humans, since systemic concentrations of tafluprost acid are extremely low (<30 pg/mL) and transient (not quantifiable (<10 pg/mL) at ≥30 minutes following ocular dosing). Therefore, specific drug interaction studies have not been performed with tafluprost.
8.2 Drug-Drug Interactions
Interactions with other drugs have not been studied. In clinical studies tafluprost was used concomitantly with timolol without evidence of an increase in the incidence of adverse events.
8.3 Drug-Food Interactions
Interactions with food have not been established.
8.4 Drug-Herb Interactions
Interactions with herbal products have not been established.
8.5 Drug-Laboratory Test Interactions
Interactions with laboratory tests have not been established.
9 ACTION AND CLINICAL PHARMACOLOGY
9.1 Mechanism of Action
Tafluprost is a fluorinated analogue of prostaglandin F2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor.
In preclinical studies tafluprost has been shown to reduce IOP in non-human primates. Studies of aqueous humor dynamics in primates indicate that the main mechanism of action for IOP reduction is increased uveoscleral outflow of aqueous humor. The effects of tafluprost on aqueous humor dynamics have not been studied in humans.
9.2 Pharmacodynamics
Dose response and dose regimen
Two dose-finding studies evaluated the effects of tafluprost given once daily (evening) in patients with elevated IOP. In the first study tafluprost 0.001%, 0.0025%, and 0.005% were tested using placebo and latanoprost as negative and positive controls, respectively. In the second study, tafluprost 0.0015% was tested, along with 0.0003%, and 0.0025%, with two positive control groups: 0.005% latanoprost and 0.5% timolol. IOP was measured up to 24-hours post-dose for both studies. From these studies, the duration of action for tafluprost was found to be beyond 24 hours.
An additional study evaluated the duration of action of 0.0015% tafluprost up to 48 hours compared with latanoprost. The mean IOP at 12 hours after the last dose administered during the study was 17 mmHg, and remained stable for up to 24 hours after the last dose.
Based on this information, a once-daily evening dosing of 0.0015% tafluprost was determined to be optimal.
Cardiovascular effects
Tafluprost in clinical doses has not been found to have any significant pharmacological effects on the cardiovascular system.
9.3 Pharmacokinetics
Absorption: Tafluprost is absorbed through the cornea where the isopropyl ester is hydrolyzed to the biologically active acid metabolite (EC50 to the recombinant human FP prostanoid receptor = 217 pg/mL). Pharmacokinetics of tafluprost acid were obtained from a study comparing preservative-containing and preservative-free ophthalmic solutions. The preservative-free formulation showed similar pharmacokinetic properties to the preservative-containing formulation. Mean plasma Cmax and AUC0-last values for the preservative-containing and preservative-free formulations on Days 1 and 8 are shown in Table . Mean plasma concentrations were below the limit of quantification at 30 minutes for both formulations.
Table 3 - Mean Tafluprost Acid Pharmacokinetic Parameters (AUC0-last and Cmax) on Days 1 and 8 Following Once Daily Dosing of Tafluprost 0.0015% (N=16)
| Formulation | Study Day | AUC0-last (pg*min/mL) | Cmax (pg/mL) |
| Preserved | Day 1 | 406 | 24 |
| Preserved | Day 8 | 581 | 31 |
| Unpreserved | Day 1 | 394 | 26 |
| Unpreserved | Day 8 | 432 | 27 |
In a rabbit study, the absorption of tafluprost into the aqueous humor was comparable after a single ocular instillation of preservative-free or preservative-containing tafluprost 0.0015% ophthalmic solution.
Distribution: After topical administration of 1mcg 3H-tafluprost on the monkey eye, the maximum radioactivity in the aqueous humor was detected at 2 hours (21-30 ng equivalents/mL) and declined to 0.3-0.4 ng equivalents/mL at 24 hours.
The binding of tafluprost acid to human serum albumin was >99%. It is anticipated that tafluprost acid will be highly protein bound in human plasma.
Metabolism: Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is further metabolized via fatty acid β-oxidation and phase II conjugation.
Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid.
Excretion: In two clinical studies, mean tafluprost acid metabolite concentrations fell below the limit of quantification in plasma (10 pg/mL) 30 minutes after administration, indicating rapid elimination.
Special Populations and Conditions
Hepatic Insufficiency: Tafluprost has not been studied in patients with hepatic insufficiency and should therefore be used with caution in such patients.
Renal Insufficiency: Tafluprost has not been studied in patients with renal insufficiency and should therefore be used with caution in such patients.
Pulmonary Insufficiency: Tafluprost has not been systematically studied in patients with pulmonary insufficiency and should therefore be used with caution in such patients.
10 STORAGE, STABILITY AND DISPOSAL
Store the unopened foil pouches of SAFLUTAN (tafluprost ophthalmic solution, 15 mcg/mL), in a refrigerator (2°C – 8°C).
Shelf life unopened foil pouch: 36 months
Shelf life opened foil pouch: 28 days
After opening the foil pouch:
- Keep the single-dose containers in the original foil pouch.
- Do not store above 25°C.
- Discard any unused single-dose containers after 28 days from date of first opening of the foil pouch.
- Discard an opened single-dose container with any remaining solution immediately after use.
- Keep in a safe place out of the reach of children.
PART II: SCIENTIFIC INFORMATION
11 PHARMACEUTICAL INFORMATION
Drug Substance
Proper name: tafluprost
Chemical name: 1-methylethyl (5Z)-7[(1R, 2R, 3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl]-3,5-dihydroxycyclopentyl]-5- heptenoate
Molecular formula and molecular mass: C25H34F2O5
452.53
Structural formula:
Physicochemical properties: Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in water.
12 CLINICAL TRIALS
12.1 Trial Design and Study Demographics
Table 4 - Summary of Patient Demographics for Clinical Trials in Specific Indication
| Study # | Trial design | Dosage, route of administration and duration | Study subjects (n=number) | Mean age (Range) (Years) | Gender |
| Study # | Trial design | Dosage, route of administration and duration | Study subjects (n=number) | Mean age (Range) (Years) | Gender |
| 001 | Multicenter, randomized, double- masked, active- controlled, parallel- group | Tafluprost 0.0015% QD (preservative-free) Timolol 0.5% BID (preservative-free) Ophthalmic; one drop in the affected eye(s) according to the regimen above 12 weeks | Tafluprost (n=320) Timolol (n=323) | Tafluprost: 63.3 (range 25-91) Timolol: 63.3 (range 21-94) | Male: 268 Female: 375 |
| 74458 | Multicenter, randomized, double- masked, active- controlled, parallel- group | Tafluprost 0.0015% Latanoprost 0.005% Ophthalmic; one drop in the affected eye(s) according to the regimen above 24 months | Tafluprost (n=269) Latanoprost (n=264) | Tafluprost: 62.5 (range 23-86) Latanoprost: 62.4 (range 18-88) | Male: 221 Female: 312 |
| 15-003 | Multicenter, randomized, double- masked, active- controlled, parallel- group | Tafluprost 0.0015% QD Timolol 0.5% BID Ophthalmic; one drop in the affected eye(s) according to the regimen above 12 months | Tafluprost (n=267) Timolol (n=191) | Tafluprost: 61.3 (range 21-88) Timolol: 61.5 (range 21-84) | Male: 187 Female: 271 |
| Study # | Trial design | Dosage, route of administration and duration | Study subjects (n=number) | Mean age (Range) (Years) | Gender |
| 77550 | Multicenter, randomized, investigator-masked, crossover | Tafluprost 0.0015 % (preserved) Tafluprost 0.0015 % (preservative-free) Ophthalmic; one drop in the affected eye(s) according to the regimen above 4 weeks | Tafluprost preserved- preservative- free sequence (n=21) Tafluprost preservative- free-preserved sequence (n=22) | 65.3 (range 35-85) | Male: 16 Female: 27 |
| 77552 | Multicenter, open-label | Tafluprost 0.0015% QD (preservative-free) Ophthalmic; one drop in the affected eye(s) according to the regimen above 12 weeks | Tafluprost unpreserved (n=158) | 68.9 (range 37-88) | Male: 54 Female: 104 |
12.2 Study Results
Clinical Effects on Intraocular Pressure
The efficacy of tafluprost as monotherapy was investigated in clinical studies of up to two years duration in patients with primary open-angle glaucoma or ocular hypertension.
Reduction of intraocular pressure starts between 2 and 4 hours after the first administration and maximum effect is reached at around 12 hours after instillation. The duration of effect is maintained for at least 24 hours. Pivotal studies with a tafluprost formulation containing the preservative benzalkonium chloride have demonstrated that tafluprost is effective as monotherapy.
Monotherapy vs. Active Comparators
The efficacy of tafluprost as monotherapy in patients with primary open-angle glaucoma or ocular hypertension (baseline IOP ≥22 mmHg) was demonstrated in three large clinical studies of up to two years duration. The primary efficacy endpoint of the studies was the intraocular pressure (IOP) change from baseline. The IOP-lowering effect of tafluprost was demonstrated throughout the day and this effect was maintained during long-term administration.
In a 12-week randomized, double-masked, active-controlled, parallel-group, multinational study (baseline IOP range of 23 to 36 mmHg), preservative-free tafluprost 0.0015% q.d. (N=320) reduced IOP from baseline by 6 to 9 mmHg throughout the study as compared to 5 to 8 mmHg with preservative-free timolol 0.5% b.i.d. (N=323). The IOP-lowering effect of tafluprost was non-inferior to that of timolol at all visits and time points.
Table 5 - IOP by Visit and Time Point (Protocol 001)
| Visit | Time Point | Tafluprost 0.0015% Mean (SD) Change Na mmHg (% Change)b | Timolol Maleate 0.5% Mean (SD) Change Na mmHg (% Change)b |
| Baseline | 8:00 10:00 16:00 | 299 26.1 (2.7) -- 299 24.8 (3.3) -- 296 23.8 (3.3) -- | 313 26.0 (2.5) -- 313 24.6 (2.9) -- 312 23.5 (3.1) -- |
| Week 2 | 8:00 10:00 16:00 | 280 18.9 (3.1) -7.1 (-27.3) 293 18.0 (2.9) -6.8 (-27.2) 292 17.5 (3.1) -6.2 (-25.7) | 295 19.2 (3.3) -6.8 (-25.8) 305 18.5 (3.2) -6.1 (-24.1) 303 18.3 (3.0) -5.3 (-21.7) |
| Week 6 | 8:00 10:00 16:00 | 294 18.8 (3.0) -7.3 (-27.7) 298 17.7 (3.1) -7.0 (-28.1) 298 17.3 (3.2) -6.3 (-26.3) | 308 18.6 (3.2) -7.4 (-28.1) 312 18.0 (3.0) -6.6 (-26.2) 311 18.1 (3.0) -5.5 (-22.7) |
| Week 12 | 8:00 10:00 16:00 | 296 18.6 (3.1) -7.4 (-28.5) 298 17.7 (2.9) -7.0 (-28.3) 298 17.4 (2.9) -6.2 (-25.9) | 308 18.5 (3.2) -7.5 (-28.5) 312 18.0 (3.2) -6.6 (-26.4) 311 17.9 (3.2) -5.7 (-23.3) |
a. N = Number of patients included in the analysis at the corresponding visit and time point.
b. Mean absolute change (mmHg) and percentage change (%) from baseline.
Analysis details: Per-protocol population; Analysis of covariance; Worse eye.
In a 6-month randomized, double-masked, active-controlled, parallel-group, multinational study (baseline IOP range of 22 to 34 mmHg), tafluprost 0.0015% q.d. (N=269) showed a significant IOP-lowering effect from baseline of 7 to 8 mmHg at Month 6 as compared to 7 to 9 mmHg with latanoprost 0.005% q.d. (N=264). The IOP-lowering effect of tafluprost was sustained in the extension of this study up to 24 months. However, tafluprost did not reach the predetermined criterion for non-inferiority versus latanoprost.
Table 6 - IOP by Visit and Time Point (Protocol 74458)
| Visit | Time Point | Tafluprost 0.0015% Mean (SD) Change Na mmHg (% Change)b | Latanoprost 0.005% Mean(SD) Change Na mmHg (% Change)b |
| Baseline | 8:00 12:00 16:00 20:00 | 264 25.8 (2.9) -- 264 24.5 (3.4) -- 263 23.6 (3.7) -- 264 23.2 (3.7) -- | 264 25.3 (2.9) -- 264 24.2 (3.0) -- 264 23.1 (3.5) -- 264 22.8 (3.6) -- |
| Week 2 | 8:00 | 264 17.7 (3.3) -8.1 (-31.4) | 264 16.7 (3.2) -8.6 (-33.7) |
| Week 6 | 8:00 | 263 17.8 (3.4) -8.0 (-30.8) | 260 16.6 (3.0) -8.7 (-34.0) |
| Month 3 | 8:00 12:00 16:00 20:00 | 254 17.6 (3.3) -8.3 (-31.8) 252 17.1 (3.1) -7.3 (-29.5) 250 16.7 (3.0) -6.9 (-28.4) 252 16.8 (2.9) -6.3 (-26.3) | 256 16.2 (2.9) -9.1 (-35.7) 256 15.8 (2.9) -8.4 (-34.3) 254 15.9 (2.8) -7.2 (-30.5) 255 15.8 (2.8) -7.0 (-29.8) |
| Month 6 | 8:00 12:00 16:00 20:00 | 244 17.8 (3.5) -8.1 (-31.0) 242 17.3 (3.2) -7.1 (-28.6) 243 17.0 (3.1) -6.7 (-27.5) 243 16.8 (3.1) -6.3 (-26.5) | 251 16.1 (3.0) -9.2 (-35.9) 251 15.7 (2.9) -8.5 (-34.3) 248 15.6 (2.9) -7.5 (-31.8) 248 15.8 (2.7) -7.1 (-30.0) |
| Month 9 | 8:00 | 242 18.0 (3.6) -7.8 (-30.0) | 250 16.4 (2.9) -8.9 (-34.8) |
| Month 12 | 8:00 12:00 16:00 20:00 | 227 18.1 (3.7) -7.6 (-29.4) 224 17.3 (3.4) -7.0 (-28.3) 222 17.2 (3.4) -6.2 (-25.7) 220 17.2 (3.4) -5.8 (-24.2) | 247 16.3 (3.0) -9.0 (-35.1) 246 15.9 (3.0) -8.3 (-33.7) 244 15.7 (3.0) -7.3 (-30.8) 243 16.0 (3.3) -6.7 (-28.5) |
| Month 15 | 8:00 | 192 17.4 (3.5) -8.2 (-31.8) | 224 15.8 (2.7) -9.4 (-36.9) |
| Month 18 | 8:00 12:00 16:00 20:00 | 188 17.2 (3.4) -8.4 (-32.7) 186 16.6 (3.1) -7.5 (-30.5) 185 16.5 (3.1) -6.9 (-28.8) 184 16.5 (3.1) -6.4 (-27.0) | 220 15.9 (3.2) -9.3 (-36.4) 218 15.9 (3.0) -8.2 (-33.4) 219 15.6 (3.0) -7.3 (-31.0) 218 15.7 (3.1) -6.8 (-29.2) |
| Month 24 | 8:00 12:00 16:00 20:00 | 185 17.6 (4.0) -8.0 (-31.3) 186 16.9 (3.7) -7.2 (-29.4) 183 16.8 (3.4) -6.6 (-27.4) 181 16.7 (3.4) -6.3 (-26.5) | 217 16.1 (2.9) -9.0 (-35.4) 216 15.8 (2.9) -8.2 (-33.6) 216 15.9 (2.9) -7.0 (-29.7) 212 15.8 (2.9) -6.6 (-28.5) |
a. N = Number of patients included in the analysis at the corresponding visit and time point.
b. Mean absolute change (mmHg) and percentage change (%) from baseline.
Analysis details: Intention-to-treat population; Repeated measurements analysis of covariance; Worse eye.
In a second 6-month randomized, double-masked, active-controlled, parallel-group, multicenter clinical study conducted in the U.S. (baseline IOP range of 22 to 34 mmHg), tafluprost 0.0015% q.d. (N=267) and timolol 0.5% b.i.d. (N=191) each reduced IOP from baseline by 5 to 7 mmHg at Month 6. The IOP-lowering effect of tafluprost was sustained in the extension of this study up to 12 months and was non-inferior to that of timolol at all visits and time points.
Table 7 - IOP by Visit and Time Point (Protocol 15-003)
| Visit | Time Point | Tafluprost 0.0015% Mean (SD) Change Na mmHg (% Change)b | Timolol Maleate 0.5% Mean (SD) Change Na mmHg (% Change) b |
| Baseline | 8:00 10:00 | 265 25.6 (3.1) -- 265 23.5 (3.6) -- | 187 25.6 (3.2) -- 187 23.8 (3.8) -- |
| Week 2 | 8:00 10:00 | 265 18.6 (3.3) -7.0 (-26.8) 77 17.4 (3.0) -6.1 (-24.8) | 187 19.1 (3.4) -6.5 (-25.0) 62 17.7 (2.9) -5.9 (-23.9) |
| Week 6 | 8:00 10:00 | 260 18.6 (3.2) -7.1 (-27.2) 141 17.3 (3.2) -5.7 (-24.0) | 185 18.6 (3.5) -6.9 (-26.8) 105 17.5 (3.1) -6.0 (-24.5) |
| Month 3 | 8:00 10:00 | 257 19.0 (3.4) -6.7 (-25.8) 257 17.8 (3.2) -5.7 (-23.7) | 180 19.3 (3.9) -6.3 (-24.4) 179 17.9 (3.5) -5.9 (-24.1) |
| Month 6 | 8:00 10:00 | 251 19.0 (3.4) -6.6 (-25.4) 251 17.9 (3.3) -5.5 (-22.9) | 171 19.0 (3.7) -6.5 (-25.2) 172 18.0 (3.4) -5.6 (-23.1) |
| Month 9 | 8:00 10:00 | 247 18.4 (3.3) -7.2 (-27.8) 246 17.7 (3.2) -5.8 (-24.0) | 165 18.9 (3.3) -6.5 (-25.3) 165 18.0 (3.3) -5.5 (-22.6) |
| Month 12 | 8:00 10:00 | 240 18.9 (3.5) -6.7 (-25.7) 239 17.8 (3.4) -5.6 (-23.0) | 162 18.5 (3.1) -6.8 (-26.7) 159 17.8 (3.3) -5.5 (-22.7) |
a. N = Number of patients included in the analysis at the corresponding visit and time point.
b. Mean absolute change (mmHg) and percentage change (%) from baseline.
Analysis details: Intention-to-treat population; Repeated measurements analysis of covariance; Worse eye.
Preservative-free vs. Preservative-containing
In a small 4-week randomized, investigator-masked, multinational crossover study (baseline IOP range of 22 to 34 mmHg), the IOP-lowering effect of preservative-free tafluprost 0.0015% q.d. was compared with the preservative-containing formulation (N=43). Patients were dosed for 4 weeks with the preservative-free and for 4 weeks with the preservative-containing formulation in crossover fashion, with an intervening washout period. Compared to baseline values, the
preservative-containing and the preservative-free formulations of tafluprost showed a similar IOP-lowering effect of 5 to 6 mmHg at Week 4. Both the preservative-free and preservative- containing formulations were generally well-tolerated.
Table 8 - IOP by Visit and Time Point (Protocol 77550)
| Visit | Time Point | Tafluprost Preserved Formulation Mean (SD) Change Na mmHg (% Change)b | Tafluprost Preservative-free Formulation Mean (SD) Change Na mmHg (% Change)b |
| Baseline | 8:00 12:00 16:00 20:00 | 42 22.6 (3.0) -- 42 20.9 (2.8) -- 42 21.7 (3.2) -- 42 21.8 (3.0) -- | 43 23.0 (3.2) -- 43 21.8 (2.7) -- 43 21.5 (2.5) -- 43 21.8 (2.6) -- |
| Week 1 | 8:00 12:00 16:00 20:00 | 42 16.4 (2.1) -6.1 (-26.2) 42 15.8 (1.6) -5.1 (-23.3) 42 16.2 (1.7) -5.5 (-23.4) 42 16.3 (2.2) -5.5 (-24.8) | 43 16.2 (2.7) -6.8 (-28.9) 43 15.7 (1.9) -6.1 (-27.3) 43 15.8 (2.0) -5.7 (-25.8) 43 16.2 (2.1) -5.7 (-25.2) |
| Week 4 | 8:00 12:00 16:00 20:00 | 42 16.4 (2.4) -6.2 (-26.6) 42 16.3 (2.5) -4.6 (-21.0) 42 16.6 (2.4) -5.1 (-22.3) 42 17.2 (1.9) -4.6 (-19.9) | 43 16.8 (3.0) -6.2 (-26.6) 43 16.7 (2.5) -5.1 (-23.1) 43 16.7 (2.5) -4.8 (-21.6) 43 17.0 (2.4) -4.8 (-21.3) |
a. N = Number of patients included in the analysis at the corresponding visit and time point.
b. Mean absolute change (mmHg) and percentage change (%) from baseline.
Analysis details: Intention-to-treat population; Repeated measurements analysis of covariance; Worse eye.
Open-label Preservative-free Crossover Study (Protocol 77552)
The tolerability and IOP-reducing effect of preservative-free tafluprost was investigated in an open-label, phase IIIb study of 158 patients exhibiting ocular surface signs or symptoms during latanoprost 0.005% treatment. Preservative-free tafluprost 0.0015% maintained IOP at the same level after 12 weeks treatment as latanoprost at baseline. After switching to tafluprost, the number of patients with abnormal Schirmer’s test was significantly reduced, and, tear break-up time improved significantly. A reduction in the number of patients with abnormal conjunctival cells based on HLA-DR and MUC5AC was also detected. Patients had fewer ocular signs or symptoms while taking preservative-free tafluprost than while taking latanoprost.
Table 9 - Mean IOP of the Treated Eyes during the Study
Baseline (N=158) Mean (SD) | 2 weeks (N=157) Mean (SD) | 6 weeks (N=156) Mean (SD) | 12 weeks (N=155) Mean (SD) | |
| IOP (mmHg) | 16.77 (2.52) | 16.23 (2.42) | 16.36 (2.52) | 16.44 (2.69) |
Table 10 - Tear Secretion/Schirmer Test at Baseline, Week 6 and Week 12
Baseline (N=158) Mean (SD) | Week 6 (N=156) Mean (SD) | Week 12 (N=155) Mean (SD) | |
| Tear secretion/Schirmer test (mm) | 9.6 (8.17) | 10.9 (9.54) | 10.5 (8.97) |
Table 11 - Tear Break-Up Time (tBUT) at Baseline, Week 6 and Week 12
Baseline (N=158) Mean (SD) | Week 6 (N=156) Mean (SD) | Week 12 (N=155) Mean (SD) | |
| Tear break-up time (seconds) | 4.5 (2.49) | 6.7 (4.31) | 7.8 (4.86) |
Table 12 - Number (percentage) of Patients With Abnormal Levels of HLA-DR-Positive Epithelial Cells at Baseline, Week 6 and Week 12
| Abnormala at Baseline (N=152) | Abnormala at 6 weeks (N=151) | Abnormala at 12 weeks (N=152) | |
| HLA-DR-positive epithelial cells | 100 (65.8%) | 68 (45.0%) | 87 (57.2%) |
a. ≥ 40% of HLA-DR positive cells
Table 13 - Number (percentage) of Patients with Abnormal Levels of MUC5AC-Expressing Goblet Cells at Baseline, Week 6 and Week 12
| Abnormala at Baseline (N=142) | Abnormala at 6 weeks (N=146) | Abnormala at 12 weeks (N=150) | |
| MUC5AC-expressing goblet cells | 99 (69.7%) | 75 (51.4%) | 77 (51.3%) |
a. < 7% of cells positive to the mucin marker, related to MUC5AC-expressing cells
Table 14 - Number (Percentage) of Patients with Abnormal Ocular Signs at Baseline, Week 6 and Week 12
| Ocular Sign (worse eye) | Abnormala at Baseline (N=158) | Abnormala at 6 weeks (N=156) | Abnormala at 12 weeks (N=155) |
| Tear break-up time (tBUT) | 150 (94.9%) | 120 (76.9%) | 111 (71.6%) |
| Corneal fluorescein staining | 129 (81.6%) | 82 (52.6%) | 63 (40.6%) |
| Conjunctival fluorescein staining | 133 (84.2%) | 84 (53.8%) | 67 (43.2%) |
| Blepharitis | 95 (60.1%) | 66 (42.3%) | 63 (40.6%) |
| Conjunctival redness/hyperemia | 133 (84.2%) | 108 (69.2%) | 93 (60.0%) |
| Tear secretion/Schirmer test | 113 (71.5%) | 96 (61.5%)b | 92 (59.4%)b |
a. tBUT < 10 sec; At least grade I corneal staining; At least grade II combined (nasal and temporal)
conjunctival staining; At least mild blepharitis; At least mild conjunctival redness; Schirmer test value 10 mm or less.
b. p=0.014 at 6 weeks and p=0.003 at 12 weeks for tear secretion (from McNemar’s test for changes from baseline in proportions). For all other signs at both visits, the p-values were < 0.001.
Table 15 - Number (Percentage) of Patients with Abnormal Ocular Symptoms at Baseline, Week 6 and Week 12
| Ocular Symptom | Abnormala at Baseline (N=158) | Abnormala at 6 weeks (N=156) | Abnormala at 12 weeks (N=155) |
| Irritation/burning/stinging | 89 (56.3%) | 48 (30.8%) | 44 (28.4%) |
| Foreign body sensation | 78 (49.4%) | 45 (28.8%) | 42 (27.1%) |
| Tearing | 87 (55.1%) | 40 (25.6%) | 42 (27.1%) |
| Itching | 74 (46.8%) | 40 (25.6%) | 41 (26.5%) |
| Dry eye sensation | 102 (64.6%) | 55 (35.3%) | 61 (39.4%) |
a. At least mild severity grading.
13 NON-CLINICAL TOXICOLOGY
Animal Pharmacology
When rabbits were treated for 4 weeks with a tafluprost 0.0015% ophthalmic solution once daily, the optic nerve head blood flow was significantly increased compared to baseline when measured by the laser speckle flowgraphy on Days 14 and 28.
Chronic Toxicity
As with other PGF2 agonists, repeated dose topical ocular administration of tafluprost to monkeys produced irreversible effects on iris pigmentation and reversible enlargement of the palpebral fissure.
Carcinogenicity
Tafluprost was not carcinogenic when administered subcutaneously daily for 24 months at doses up to 30 mcg/kg/day in rats and for 18 months at doses up to 100 mcg/kg/day in mice (over 1600- and 1300-times, respectively, the maximum clinical exposure based on plasma AUC).
Mutagenesis
Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse micronucleus assay in bone marrow.
Reproduction
In rats, no adverse effects on mating performance, fertility or early embryonic development were observed with intravenous dosing of tafluprost at systemic exposure over 14000-times the maximum clinical exposure based on Cmax or greater than 3600-times based on AUC.
Development
In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously caused increases in post-implantation losses in rats and rabbits and reductions in fetal body weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a dose of 3 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid that were 343-times the maximum clinical exposure based on Cmax. In rabbits, effects were seen at tafluprost dose of 0.03 mcg/kg/day corresponding to maternal plasma levels of tafluprost acid during the critical period of development that were 5.3-times higher than the clinical exposure based on Cmax. At the no effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below the lower level of quantification (20 pg/mL).
In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and delayed pinna unfolding were observed in offspring at tafluprost doses greater than 20-times the clinical dose. The no observed adverse effect level was at a tafluprost intravenous dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface area comparison.