Zioptan于2012年2月14日获FDA批准上市，是首个不含防腐剂的前列腺素类似物的滴眼药，应用于开角型青光眼或高眼压患者，降低眼内压。

Zioptan (tafluprost)眼溶液–曾用名Saflutan

批准日期：2012年2月10日：公司：Merck & Co., Inc.

为治疗：青光眼(开角型), 眼内高压

Zioptan(tafluprost眼溶液)是一种前列腺素类似物适用于在患开角型青光眼或眼高压患者中减低升高的眼内压。

Merck公司在美国和加拿大称为MSD外今天宣布美国食品药品监督管理局(FDA)已批准Zioptan (tafluprost眼溶液)0.0015%,。第一个无防腐剂前列腺素类似物眼科溶液，Zioptanis 被批准为in患开角型青光眼(OAG)或眼高压患者中减低升高的眼内压(IOP)。开角型青光眼是一种最常见的青光眼型，当眼高压是通过增加眼内压为特征的一种情况。

滨州眼科研究所Wills George L. Spaeth, M.D.说“前列腺素类似物是常被用作对患开角型青光眼患者中降低眼内压的一线治疗。被批准扎Zioptan将为降低IOP提供一种新，有效选择。”“我期望在我的这些许多患者实践中用Zioptan。”
Zioptan可能逐渐改变被治疗眼眼睫毛和毫毛。这些变化包括长度增加，颜色，厚度，形状和睫毛数。治疗终止睫毛变化通常是可逆的。
FDA批准Zioptan是根据来自在905例患者直至两年的五项对照临床研究疗效和安全结果。这些临床研究使用含防腐剂和无防腐剂的两种tafluprost制剂。
Zioptan被显示有强有力的降IOP作用。在长达2年时间的临床研究中，Zioptan，在傍晚给药每天1次分别在3和6个月时降低IOP至6-8 mmHg和5-8 mmHg，从基线压23-26 mmHg (mmHg = 毫米汞柱，对眼内压的测量).
Merck研究实验室神经学和眼科治疗领域副总裁David Michelson, M.D.说“Zioptan是第一个无防腐剂前列腺素类似物， ”“我们很高兴继续Merck公司50-年传统提出另外选择帮助专业人员和其患者眼科医护需求。."

Merck公司期望在三月份推出Zioptan。

部份处方资料重点

ZIOPTAN™ (tafluprost眼溶液) 0.0015%

适应证和用途
（1）ZIOPTAN(tafluprost眼溶液) 0.0015% 是一种前列腺素类似物适用于开角型青光眼或眼高压患者中减低升高的眼内压。
 
剂量和给药方法

（1）在患眼(s)中一滴每天1次在傍晚。

剂型和规格

（1）含tafluprost眼溶液0.015 mg/mL。

禁忌证

（1）无。

警告和注意事项

（1）色素沉着

可能发生虹膜，眼周组织(眼睑)和眼睫毛色素沉着。虹膜色素沉着很可能是永久性的。

（2）睫毛变化

对眼睫毛包括长度，厚度增加逐渐改变和睫毛数. Usually reversible.

不良反应
（1） 最常见眼不良反应是结膜充血(范围4%–20%)。

特殊人群中使用

（1）建议儿童患者不要使用因为长期慢性使用后色素沉着增加相关的潜在的安全性关注。

一般描述

Tafluprost是一种前列腺素F2α氟化的类似物。Tafluprost的化学名是1methylethyl (5Z)-7-{(1R, 2R, 3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl}-3,5-dihydroxycyclopentyl]5-heptenoate. Tafluprost的分子式是C25H34F2O5和其分子量452.53。结构式是：

作用机制
Tafluprost酸，一种前列腺素类似物是一种选择性FP前列腺素受体激动剂，被认为通过增加葡萄膜鞏膜流出减低眼内压.。目前确切作用机制不清楚。

临床研究
在直至24个月时间的临床研究，患开角型青光眼或眼高压患者和基线压力23 - 26 mm Hg，用ZIOPTAN治疗在傍晚每天1次给药证实在3和6个月时眼内压分别减低6 – 8 mmHg和5 – 8 mmHg。

SAFLUTAN® 15 micrograms/ml eye drops, solution, single-dose container

2. QUALITATIVE AND QUANTITATIVE COMPOSITION
 One ml of eye drops, solution, contains 15 micrograms of tafluprost.

One single-dose container (0.3 ml) of eye drops, solution, contains 4.5 micrograms of tafluprost.

For a full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM
 Eye drops, solution, single-dose container (eye drops).

A clear, colourless solution.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications
 Reduction of elevated intraocular pressure in open angle glaucoma and ocular hypertension.

As monotherapy in patients:

o who would benefit from preservative free eye drops

o insufficiently responsive to first line therapy

o intolerant or contra-indicated to first line therapy.

As adjunctive therapy to beta-blockers.

4.2 Posology and method of administration
Posology

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 may lessen the intraocular pressuree in place (see section 5.3).

Pregnancy

There are no adequate data from the use of tafluprost in pregnant women. Tafluprost can have harmful pharmacologic effects on pregnancy and/or the fetus/newborn child. Studies in animals have shown reproductive toxicity (see section 5.3). Therefore, SAFLUTAN should not be used during pregnancy unless clearly necessary (in case no other treatment options are available).

Lactation

It is unknown whether tafluprost is excreted in human milk. A study in rats has shown excretion of tafluprost in breast milk after topical administration (see section 5.3). Therefore, tafluprost should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines
 Tafluprost has no influence on the ability to drive and use machines. 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.

4.8 Undesirable effects
 In clinical studies, over 1200 patients have been treated with tafluprost either as monotherapy or as adjunctive therapy to timolol 0.5%. The most frequently reported treatment-related adverse event was ocular hyperaemia. It occurred in approximately 13% of the patients participating in the clinical studies with tafluprost in Europe and the US. It was mild in most cases and led to discontinuation on an average in 0.4% of patients participating in the pivotal studies.

The following undesirable effects related to treatment were reported during clinical trials with tafluprost in Europe and the US after a maximum follow-up of 12 months:

Within each frequency grouping, adverse reactions are presented in order of decreasing frequency.

Eye disorders

Very common (1/10): conjunctival/ocular hyperaemia

Common (1/100 to <1/10): eye pruritus, eye irritation, eye pain, changes in eyelashes (increased length, thickness and number of lashes), dry eye, eyelash discolouration, foreign body sensation in eyes, erythema of eye lid, blurred vision, increased lacrimation, blepharal pigmentation, eye discharge, reduced visual acuity, photophobia, eyelid oedema and increased iris pigmentation.

Uncommon (1/1000 to <1/100): superficial punctate keratitis (SPK), asthenopia, conjunctival oedema, blepharitis, ocular discomfort, anterior chamber flare, conjunctival follicles, allergic conjunctivitis, anterior chamber cell, conjunctival pigmentation and abnormal sensation in eye.

Nervous system disorders

Common (1/100 to <1/10): headache

Skin and subcutaneous tissue disorders

Uncommon (1/1000 to <1/100): hypertrichosis of eyelid

4.9 Overdose
 No case of overdose has been reported. Overdose is unlikely to occur after ocular administration.

If overdose occurs, treatment should be symptomatic.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties
 Pharmacotherapeutic group: Antiglaucoma preparations and miotics, prostaglandin analogues

ATC code: S01EE05

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. Tafluprost acid has a 12-fold higher affinity for the FP receptor than latanoprost. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour.

Clinical effects on intraocular pressure

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 and has an additive effect when administered as adjunctive therapy to timolol: In a 6-month study, tafluprost showed a significant IOP lowering effect of 6 to 8 mmHg at different time points of the day as compared to 7 to 9 mmHg with latanoprost. In a second 6-month clinical study, tafluprost reduced IOP by 5 to 7 mmHg as compared to 4 to 6 mmHg with timolol. The IOP lowering effect of tafluprost was maintained in the extension of these studies up to 12 months. In a 6-week study, the IOP-lowering effect of tafluprost was compared with its vehicle when used adjunctively with timolol. Compared to baseline values (measured after a 4-week run in on timolol), the additional IOP-lowering effects were 5 to 6 mmHg in the timolol-tafluprost group and 3 to 4 mmHg in the timolol-vehicle group. The preserved and the non-preserved formulations of tafluprost showed a similar IOP-lowering effect of over 5 mmHg in a small cross-over study with a 4-week treatment period.

Secondary pharmacodynamics

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.

5.2 Pharmacokinetic properties
 After once daily ocular administration of one drop of unpreserved tafluprost 0.0015% eye drops in single-dose container to both eyes for 8 days, plasma concentrations were low and had similar profiles on days 1 and 8. The plasma concentrations peaked at 10 minutes after dosing and declined to below the lower limit of detection (10 pg/mL) before one hour after dosing. Mean Cmax (26.2 and 26.6 pg/mL) and AUC0-last (394.3 and 431.9 pg*min/mL) values were similar on days 1 and 8, indicating that a steady drug concentration was reached during the first week of ocular dosing. No statistically significant differences in the systemic bioavailability between the preserved and unpreserved formulation were detected.

In a rabbit study, the absorption of tafluprost into the aqueous humour was comparable after a single ocular instillation of unpreserved or preserved tafluprost 0.0015% ophthalmic solution.

In monkeys, there was no specific distribution of radiolabelled tafluprost in the iris-ciliary body or choroid including retinal pigment epithelium, which suggested low affinity for melanin pigment.

The principle metabolic pathway of tafluprost in humans is the hydrolysis to tafluprost acid and further beta-oxidation to the pharmacologically inactive 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which may be glucuronated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid.

5.3 Preclinical safety data
 Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, systemic repeated dose toxicity, genotoxicity and carcinogenic potential. 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.

Increased contraction of rat and rabbit uteri in vitro was observed at tafluprost acid concentrations that exceeded 4 to 40 times, respectively, the maximum plasma concentrations of tafluprost acid in humans. Uterotonic activity of tafluprost has not been tested in human uterus preparations.

Reproduction toxicity studies were performed in the rat and rabbit with intravenous administration. In rats, no adverse effects on fertility or early embryonic development were observed at systemic exposure over 12 000 times the maximum clinical exposure based on Cmax or greater than 75 times based on AUC.

In conventional embryo-foetal development studies, tafluprost caused reductions in foetal body weights and increases in post-implantation losses. Tafluprost increased the incidence of skeletal abnormalities in rats as well as the incidence of skull, brain and spine malformations in rabbits. In the rabbit study, plasma levels of tafluprost and its metabolites were below the level of quantification.

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 experiments in rats with radiolabelled tafluprost showed that around 0.1% of the topically applied dose on eyes was transferred into milk. As the half-life of active metabolite (tafluprost acid) in plasma is very short (not detectable after 30 minutes in humans), most of the radioactivity probably represented metabolites with little, or no pharmacologic activity. Based on metabolism of the drug and natural prostaglandins, the oral bioavailability is expected to be very low.

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients
 Glycerol

Sodium dihydrogen phosphate dihydrate

Disodium edetate

Polysorbate 80

Hydrochloric acid and/or sodium hydroxide for pH adjustment

Water for injections.

6.2 Incompatibilities
Not applicable

6.3 Shelf life
3 years.

After first opening a foil pouch: 28 days.

6.4 Special precautions for storage
Store in a refrigerator (2°C - 8°C).

After opening the foil pouch:

• Keep the single-dose containers in the original foil pouch

• Do not store above 25°C

• Discard an opened single-dose container with any remaining solution immediately after use.

6.5 Nature and contents of container
&nbs

lowering effect.

For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.

Use in elderly:

No dosage alteration in elderly patients is necessary.

Use in children and adolescents:

Tafluprost is not recommended for use in children or adolescents below age 18 due to a lack of data on safety and efficacy.

Use in renal/hepatic impairment

Tafluprost has not been studied in patients with renal/hepatic impairment and should therefore be used with caution in such patients.

Method of administration

To reduce the risk of darkening of the eyelid skin the patients should wipe 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 medicinal products administered via the ocular route.

If more than one topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.

4.3 Contraindications
Hypersensitivity to tafluprost or to any of the

excipients.

4.4 Special warnings and precautions for use
 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.

The change in iris pigmentation occurs slowly and may not be noticeable for several months. The change in eye colour has predominantly been seen in patients with mixed coloured irises, e.g. blue-brown, grey-brown, yellow-brown and green-brown. The risk of lifelong heterochromia between the eyes in unilateral cases is obvious.

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.

Caution is recommended when using tafluprost in aphakic patients, pseudophakic patients with torn posterior lens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macular oedema or iritis/uveitis.

There is no experience in patients with severe asthma. Such patients should therefore be treated with caution.

4.5 Interaction with other medicinal products and other forms of interaction
 No interactions are anticipated in humans, since systemic concentrations of tafluprost are extremely low following ocular dosing. Therefore, specific interaction studies with other medicinal products have not been performed with tafluprost.

In clinical studies tafluprost was used concomitantly with timolol without evidence of interaction.

4.6 Pregnancy and lactation
Women of childbearing potential/contraception

SAFLUTAN must not be used in women of childbearing age/potential unless adequate contraceptive measures arp;Low-density polyethylene (LDPE) single-dose containers packed in foil pouch. Each single-dose container has a fill volume of 0.3 ml and there are 10 containers in each foil pouch.

The following pack sizes are available: 30 x 0.3 ml single-dose containers and 90 x 0.3 ml single-dose containers.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling
 No special requirements.

7. MARKETING AUTHORISATION HOLDER
 Merck Sharp & Dohme Limited

Hertford Road

Hoddesdon

Hertfordshire

EN11 9BU, UK
 
SAFLUTAN 15 micrograms/ml eye drops, solution, single-dose container