` NDA 202514/S003
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` NDA 202514/S004
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` Page 6
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` HIGHLIGHTS OF PRESCRIBING INFORMATION
`-----------------------WARNINGS AND PRECAUTIONS ----------------------
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` These highlights do not include all the information needed to use
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` Pigmentation
` ZIOPTAN® (tafluprost ophthalmic solution) 0.0015% safely and
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`Pigmentation of the iris, periorbital tissue (eyelid) and eyelashes can
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`effectively. See full prescribing information for ZIOPTAN®.
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`occur. Iris pigmentation is likely to be permanent. (5.1)
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` Eyelash Changes
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`Gradual changes to eyelashes including increased length, thickness
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`and number of lashes. Usually reversible. (5.2)
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`------------------------------ADVERSE REACTIONS -----------------------------
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` Most common ocular adverse reaction is conjunctival hyperemia
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`(range 4% – 20%). (6.1)
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`To report SUSPECTED ADVERSE REACTIONS, contact Akorn Inc.
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`1-800-932-5676
`FDA
`1-800-FDA-1088
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`www.fda.gov/medwatch.
`-----------------------USE IN SPECIFIC POPULATIONS ----------------------
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` Use in pediatric patients is not recommended because of potential
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`safety concerns related to increased pigmentation following long-term
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`chronic use. (8.4)
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`ZIOPTAN® (tafluprost ophthalmic solution) 0.0015%
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`Initial U.S. Approval: 2012
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`----------------------------INDICATIONS AND USAGE---------------------------
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`(tafluprost ophthalmic solution) 0.0015%
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`prostaglandin analog
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`pressure in patients with open-angle glaucoma or ocular hypertension.
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`(1)
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` One drop in the affected eye(s) once daily in the evening. (2)
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`---------------------DOSAGE FORMS AND STRENGTHS --------------------
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` Ophthalmic solution containing tafluprost 0.015 mg/mL. (3)
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`-------------------------------CONTRAINDICATIONS------------------------------
` None. (4)
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`FULL PRESCRIBING INFORMATION: CONTENTS*
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`1
`INDICATIONS AND USAGE
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`2 DOSAGE AND ADMINISTRATION
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`3 DOSAGE FORMS AND STRENGTHS
`4 CONTRAINDICATIONS
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`5 WARNINGS AND PRECAUTIONS
`5.1 Pigmentation
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`5.2 Eyelash Changes
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`Intraocular Inflammation
`5.3
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`5.4 Macular Edema
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`6 ADVERSE REACTIONS
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`6.1 Clinical Studies Experience
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`6.2 Postmarketing Experience
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`8 USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
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`8.3 Nursing Mothers
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`8.4 Pediatric Use
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`8.5 Geriatric Use
` FULL PRESCRIBING INFORMATION
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`See 17 for PATIENT COUNSELING INFORMATION and FDA-
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`approved patient labeling.
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`Revised: 08/2014
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`11 DESCRIPTION
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
`12.3 Pharmacokinetics
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`14 CLINICAL STUDIES
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`17 PATIENT COUNSELING INFORMATION
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`17.1 Nightly Application
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`17.2 Handling the Single-Use Container
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`17.3 Potential for Pigmentation
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`17.4 Potential for Eyelash Changes
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`17.5 When to Seek Physician Advice
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`17.6 Use with Other Ophthalmic Drugs
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`17.7 Storage Information
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`*Sections or subsections omitted from the full prescribing information
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`are not listed.
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`1
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`INDICATIONS AND USAGE
`ZIOPTAN® (tafluprost ophthalmic solution) 0.0015% is indicated for reducing elevated intraocular pressure in
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`patients with open-angle glaucoma or ocular hypertension.
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`2
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`DOSAGE AND ADMINISTRATION
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`The recommended dose is one drop of ZIOPTAN® in the conjunctival sac of the affected eye(s) once daily in the
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`evening.
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`The dose should not exceed once daily since it has been shown that more frequent administration of prostaglandin
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`analogs may lessen the intraocular pressure lowering effect.
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`Reduction of the intraocular pressure starts approximately 2 to 4 hours after the first administration with the
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`maximum effect reached after 12 hours.
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`Reference ID: 3814364
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` ZIOPTAN® may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If
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` more than one topical ophthalmic product is being used, each one should be administered at least 5 minutes apart.
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` The solution from one individual unit is to be used immediately after opening for administration to one or both eyes.
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` Since sterility cannot be maintained after the individual unit is opened, the remaining contents should be discarded
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` immediately after administration.
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` DOSAGE FORMS AND STRENGTHS
` Ophthalmic solution containing tafluprost 0.015 mg/mL.
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`CONTRAINDICATIONS
`None.
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` 5 WARNINGS AND PRECAUTIONS
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`5.1 Pigmentation
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` Tafluprost ophthalmic solution has been reported to cause changes to pigmented tissues. The most frequently
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` reported changes have been increased pigmentation of the iris, periorbital tissue (eyelid) and eyelashes. Pigmentation is
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` expected to increase as long as tafluprost is administered. The pigmentation change is due to increased melanin content
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` in the melanocytes rather than to an increase in the number of melanocytes. After discontinuation of tafluprost,
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` pigmentation of the iris is likely to be permanent, while pigmentation of the periorbital tissue and eyelash changes have
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` been reported to be reversible in some patients. Patients who receive treatment should be informed of the possibility of
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` increased pigmentation. The long term effects of increased pigmentation are not known.
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` Iris color change may not be noticeable for several months to years. Typically, the brown pigmentation around the
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` pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish.
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` Neither nevi nor freckles of the iris appear to be affected by treatment. While treatment with ZIOPTAN® can be continued
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`in patients who develop noticeably increased iris pigmentation, these patients should be examined regularly. [See Patient
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`Counseling Information (17.3)].
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`5.2 Eyelash Changes
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`ZIOPTAN® may gradually change eyelashes and vellus hair in the treated eye. These changes include increased
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`length, color, thickness, shape and number of lashes. Eyelash changes are usually reversible upon discontinuation of
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`treatment.
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`5.3
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`Intraocular Inflammation
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`ZIOPTAN® should be used with caution in patients with active intraocular inflammation (e.g., iritis/uveitis) because
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`the inflammation may be exacerbated.
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`5.4 Macular Edema
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`Macular edema, including cystoid macular edema, has been reported during treatment with prostaglandin F2α
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`analogs. ZIOPTAN® should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens
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`capsule, or in patients with known risk factors for macular edema.
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`6
`ADVERSE REACTIONS
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`6.1 Clinical Studies Experience
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`Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the
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`clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect
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`the rates observed in practice.
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`Preservative-containing or preservative-free tafluprost 0.0015% was evaluated in 905 patients in five controlled
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`clinical studies of up to 24-months duration. The most common adverse reaction observed in patients treated with
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`tafluprost was conjunctival hyperemia which was reported in a range of 4% to 20% of patients. Approximately 1% of
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`patients discontinued therapy due to ocular adverse reactions.
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`Ocular adverse reactions reported at an incidence of ≥ 2% in these clinical studies included ocular stinging/irritation
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`(7%), ocular pruritus including allergic conjunctivitis (5%), cataract (3%), dry eye (3%), ocular pain (3%), eyelash
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`darkening (2%), growth of eyelashes (2%) and vision blurred (2%).
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`Reference ID: 3814364
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`Nonocular adverse reactions reported at an incidence of 2% to 6% in these clinical studies in patients treated with
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`tafluprost 0.0015% were headache (6%), common cold (4%), cough (3%) and urinary tract infection (2%).
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`6.2 Postmarketing Experience
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`The following adverse reactions have been identified during postapproval use of tafluprost. Because postapproval
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`adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate
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`their frequency or establish a causal relationship to drug exposure.
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`Respiratory disorders: exacerbation of asthma, dyspnea
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`Eye disorders: iritis/uveitis
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`In postmarketing use with prostaglandin analogs, periorbital and lid changes including deepening of the eyelid
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`sulcus have been observed.
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`8
`USE IN SPECIFIC POPULATIONS
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`8.1 Pregnancy
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`Pregnancy Category C.
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`Teratogenic effects: In embryo-fetal development studies in rats and rabbits, tafluprost administered intravenously
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`was teratogenic. Tafluprost caused increases in post-implantation losses in rats and rabbits and reductions in fetal body
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`weights in rats. Tafluprost also increased the incidence of vertebral skeletal abnormalities in rats and the incidence of
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`skull, brain and spine malformations in rabbits. In rats, there were no adverse effects on embryo-fetal development at a
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`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 a tafluprost dose of 0.03 mcg/kg/day corresponding to maternal
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`plasma levels of tafluprost acid during organogenesis that were approximately 5 times higher than the clinical exposure
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`based on Cmax. At the no-effect dose in rabbits (0.01 mcg/kg/day), maternal plasma levels of tafluprost acid were below
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`the lower level of quantification (20 pg/mL).
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`In a pre- and postnatal development study in rats, increased mortality of newborns, decreased body weights and
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`delayed pinna unfolding were observed in offsprings. The no observed adverse effect level was at a tafluprost intravenous
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`dose of 0.3 mcg/kg/day which is greater than 3 times the maximum recommended clinical dose based on body surface
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`area comparison.
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`There are no adequate and well-controlled studies in pregnant woman. Although animal reproduction studies are
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`not always predictive of human response, ZIOPTAN should not be used during pregnancy unless the potential benefit
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`justifies the potential risk to the fetus.
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`Women of childbearing age/potential should have adequate contraceptive measures in place.
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`8.3 Nursing Mothers
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`A study in lactating rats demonstrated that radio-labeled tafluprost and/or its metabolites were excreted in milk. It is
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`not known whether this drug or its metabolites are excreted in human milk. Because many drugs are excreted in human
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`milk, caution should be exercised when ZIOPTAN® is administered to a nursing woman.
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`8.4 Pediatric Use
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`Use in pediatric patients is not recommended because of potential safety concerns related to increased
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`pigmentation following long-term chronic use.
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`8.5 Geriatric Use
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`No overall clinical differences in safety or effectiveness have been observed between elderly and other adult
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`patients.
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`11 DESCRIPTION
`Tafluprost is a fluorinated analog of prostaglandin F2α. The chemical name for tafluprost is 1-methylethyl (5Z)-7
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`{(1R, 2R, 3R, 5S)-2-[(1E)-3,3-difluoro-4-phenoxy-1-butenyl}-3,5-dihydroxycyclopentyl]-5-heptenoate. The molecular
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`formula of tafluprost is C25H34F2O5 and its molecular weight is 452.53.
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`Reference ID: 3814364
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`8
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`Its structural formula is:
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`Tafluprost is a colorless to light yellow viscous liquid that is practically insoluble in water.
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`ZIOPTAN® (tafluprost ophthalmic solution) 0.0015% is supplied as a sterile solution of tafluprost with a pH range of
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`5.5 to 6.7 and an Osmolality range of 260 to 300 mOsmol/kg.
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`ZIOPTAN® contains Active: tafluprost 0.015 mg/mL; Inactives: glycerol, sodium dihydrogen phosphate dihydrate,
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`disodium edetate, polysorbate 80, hydrochloric acid and/or sodium hydroxide (to adjust pH) and Water for Injection.
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`ZIOPTAN® does not contain a preservative.
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`12 CLINICAL PHARMACOLOGY
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`12.1 Mechanism of Action
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`Tafluprost acid, a prostaglandin analog is a selective FP prostanoid receptor agonist which is believed to reduce
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`intraocular pressure by increasing uveoscleral outflow. The exact mechanism of action is unknown at this time.
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`12.3 Pharmacokinetics
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`Absorption
`Following instillation, tafluprost is absorbed through the cornea and is hydrolyzed to the biologically active acid
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`metabolite, tafluprost acid. Following instillation of one drop of the 0.0015% solution once daily into each eye of healthy
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`The mean plasma Cmax of tafluprost acid were 26 pg/mL and 27 pg/mL on Day 1, and Day 8, respectively. The mean
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`plasma AUC estimates of tafluprost acid were 394 pg*min/mL and 432 pg*min/mL on Day 1 and 8, respectively.
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`Metabolism
`Tafluprost, an ester prodrug, is hydrolyzed to its biologically active acid metabolite in the eye. The acid metabolite is
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`further metabolized via fatty acid β-oxidation and phase II conjugation.
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`Elimination
`Mean plasma tafluprost acid concentrations were below the limit of quantification of the bioanalytical assay (10
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`pg/mL) at 30 minutes following topical ocular administration of tafluprost 0.0015% ophthalmic solution.
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`13 NONCLINICAL TOXICOLOGY
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`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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`Tafluprost was not carcinogenic when administered subcutaneously daily for 24 months at doses up to
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`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,
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`the maximum clinical exposure based on plasma AUC).
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`Tafluprost was not mutagenic or clastogenic in a battery of genetic toxicology studies, including an in vitro microbial
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`mutagenesis assay, an in vitro chromosomal aberration assay in Chinese hamster lung cells, and an in vivo mouse
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`micronucleus assay in bone marrow.
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`Reference ID: 3814364
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`9
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`In rats, no adverse effects on mating performance or fertility were observed with intravenous dosing of tafluprost at
`a dose of 100 mcg/kg/day (over 14000 times the maximum clinical exposure based on plasma Cmax or over 3600 times
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`based on plasma AUC).
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`14 CLINICAL STUDIES
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`In clinical studies up to 24 months in duration, patients with open-angle glaucoma or ocular hypertension and
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`baseline pressure of 23 to 26 mm Hg who were treated with ZIOPTAN® dosed once daily in the evening demonstrated
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`reductions in intraocular pressure at 3 and 6 months of 6 to 8 mmHg and 5 to 8 mmHg, respectively.
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`16 HOW SUPPLIED/STORAGE AND HANDLING
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`ZIOPTAN® (tafluprost ophthalmic solution) 0.0015% is supplied as a sterile solution in translucent low density
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`polyethylene single-use containers packaged in foil pouches (10 single-use containers per pouch). Each single-use
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`container has 0.3 mL solution corresponding to 0.0045 mg tafluprost.
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`NDC 17478-609-30; Unit-of-Use Carton of 30.
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`NDC 17478-609-90; Unit-of-Use Carton of 90.
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`Storage:
`Store refrigerated at 2º to 8°C (36º to 46°F). During shipment ZIOPTAN® may be maintained at temperatures up to
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`40ºC (104ºF) for a period not exceeding 2 days. Mail-order prescriptions received after two days of the dispensing date
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`noted on the prescribing label should not be used. Store in the original pouch. After the pouch is opened, the single-use
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`containers may be stored in the opened foil pouch for up to 30 days at room temperature 20º to 25°C (68º to 77°F).
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`Protect from moisture. Write down the date you open the foil pouch in the space provided on the pouch. Discard any
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`unused containers 30 days after first opening the pouch.
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`17 PATIENT COUNSELING INFORMATION
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`See FDA-Approved Patient Labeling (Patient Information).
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`17.1 Nightly Application
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`Advise patients to not exceed once daily dosing since more frequent administration may decrease the intraocular
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`pressure lowering effect of ZIOPTAN®.
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`17.2 Handling the Single-Use Container
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`Advise patients that ZIOPTAN® is a sterile solution that does not contain a preservative. The solution from one
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`individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be
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`maintained after the individual unit is opened, the remaining contents should be discarded immediately after
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`administration.
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`17.3 Potential for Pigmentation
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`Advise patients about the potential for increased brown pigmentation of the iris, which may be permanent. Also
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`inform patients about the possibility of eyelid skin darkening, which may be reversible after discontinuation of ZIOPTAN®.
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`17.4 Potential for Eyelash Changes
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`Inform patients of the possibility of eyelash and vellus hair changes in the treated eye during treatment with
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`ZIOPTAN®. These changes may result in a disparity between eyes in length, thickness, pigmentation, number of
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`eyelashes or vellus hairs, and/or direction of eyelash growth. Eyelash changes are usually reversible upon discontinuation
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`of treatment.
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`17.5 When to Seek Physician Advice
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`Advise patients that if they develop a new ocular condition (e.g., trauma or infection), experience a sudden
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`decrease in visual acuity, have ocular surgery, or develop any ocular reactions, particularly conjunctivitis and eyelid
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`reactions, they should immediately seek their physician’s advice concerning the continued use of ZIOPTAN®.
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`17.6 Use with Other Ophthalmic Drugs
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`If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes
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`between applications.
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`Reference ID: 3814364
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`10
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`17.7 Storage Information
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`Instruct patients on proper storage of cartons, unopened foil pouches, and opened foil pouches [see How
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`Supplied/Storage and Handling (16)]. Recommended storage for cartons and unopened foil pouches is to store
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`refrigerated at 2º to 8°C (36º to 46°F). After the pouch is opened, the single-use containers may be stored in the opened
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`foil pouch for up to 28 days at room temperature 20º to 25°C (68º to 77°F). Protect from moisture.
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`Distributed by: Akorn, Inc.
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`Manufactured for: Oak Pharmaceuticals, Inc.
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`Made in France
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`The ZIOPTAN trademark is owned by Merck
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`Sharp & Dohme Corp. and is used under license.
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`ZO00N Rev. 08/14
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`Reference ID: 3814364
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`11
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` PATIENT INFORMATION
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` ZIOPTAN® (zye OP tan)
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`(tafluprost ophthalmic solution) 0.0015%
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`Read this Patient Information before you start using ZIOPTAN® and each time you get a refill. There may be new
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`information. This information does not take the place of talking to your doctor about your medical condition or your
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`treatment.
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`What is ZIOPTAN®?
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`ZIOPTAN® is a prescription sterile eye drop solution. ZIOPTAN® is used to lower the pressure in the eye (intraocular
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`pressure) in people with open-angle glaucoma or ocular hypertension when their eye pressure is too high. ZIOPTAN®
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`belongs to a group of medicines called prostaglandin analogs.
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`ZIOPTAN® is not for use in children.
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`What should I tell my doctor before using ZIOPTAN®?
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`Before you use ZIOPTAN®, tell your doctor if you:
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` have or have had eye problems including any surgery on your eye or eyes
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` are using any other eye medicines
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` have any other medical problems
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` are pregnant or plan to become pregnant. It is not known if ZIOPTAN® will harm your unborn baby. You should
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`use an effective method of birth control while you use ZIOPTAN®. If you become pregnant while using ZIOPTAN®
`talk to your doctor right away.
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` are breastfeeding or plan to breastfeed. It is not known if ZIOPTAN® passes into your breast milk. Talk to your
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`doctor about the best way to feed your baby if you use ZIOPTAN®.
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`Tell your doctor about all the medicines you take, including prescription and non-prescription medicines, vitamins, and
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`herbal supplements.
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`Know the medicines you take. Keep a list of them to show your doctor and pharmacist when you get a new medicine.
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`How should I take ZIOPTAN®?
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`Read the Instructions for Use at the end of this Patient Information leaflet for additional instructions about the right way to
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`use ZIOPTAN®.
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`Use 1 drop of ZIOPTAN® in your eye (or eyes) each evening. Talk to your doctor or pharmacist if you
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`are not sure how to use ZIOPTAN®.
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`Your ZIOPTAN® may not work as well if you use it more than 1 time each evening.
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`If you use other medicines in your eye, wait at least 5 minutes between using ZIOPTAN® and your other
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`Use your ZIOPTAN® right away after opening. Each ZIOPTAN® single-use container is sterile and is to be
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`used 1 time then thrown away. Do not save any ZIOPTAN® that may be left over after you use your
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`medicine. Using ZIOPTAN® that is not sterile may cause other eye problems.
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`What are the possible side effects of ZIOPTAN®?
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`ZIOPTAN® may cause serious side effects including:
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` changes in the color of your eye (iris). Your iris may become more brown in color while using ZIOPTAN®. This
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`color change may not go away when you stop using ZIOPTAN®. If ZIOPTAN® is used in 1 eye only, the color of
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`that eye may always be a different color from the color of your other eye.
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`Reference ID: 3814364
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`12
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` darkening of the color of the skin around your eye (eyelid). These skin changes usually go away when you
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`stop using ZIOPTAN®.
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`increasing the length, thickness, color, or number of your eyelashes. These eyelash changes usually go
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`away when you stop using ZIOPTAN®.
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` hair growth on your eyelids. This hair growth usually goes away when you stop using ZIOPTAN®.
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`The most common side effects of ZIOPTAN® include:
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`redness, stinging or itching of your eye
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`cataract formation
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` dry eye
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` eye pain
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` blurred vision
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`common cold
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`cough
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`o urinary tract infection
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`Tell your doctor if you have any new eye problems while using ZIOPTAN® including:
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` an eye injury
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` eye surgery
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`swelling and redness of and around your eye (conjunctivitis)
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` problems with your eyelids
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`Additionally, the following side effects have been reported in general use:
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`shortness of breath
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`Tell your doctor if you have any other side effects that bother you.
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`These are not all the possible side effects of ZIOPTAN®. For more information, ask your doctor or pharmacist.
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`Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
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`How should I store ZIOPTAN®?
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`Important Information for Mail-Order Patients:
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`Do not use if prescription is not received within two days of dispensing date.
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`Keep the foil pouches and ZIOPTAN® single-use containers dry.
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`Before opening the foil pouches:
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` Store the unopened foil pouches in a refrigerator between 36°F to 46°F (2°C to 8°C).
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`Reference ID: 3814364
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`13
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` Do not open the pouch containing ZIOPTAN® until you are ready to use the eye drops.
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` After opening the foil pouch:
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` Store the opened foil pouch at room temperature, between 68°F to 77°F (20°C to 25°C), for up to 30 days.
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` Throw away all unused ZIOPTAN® single-use containers in the opened foil pouch after 30 days.
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` Keep the ZIOPTAN® single-use containers in their original foil pouch.
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` After opening the foil pouch, refrigeration is not required.
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`Keep ZIOPTAN® and all medicines out of the reach of children.
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`General information about the safe and effective use of ZIOPTAN®.
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`Do not use ZIOPTAN® for a condition for which it was not prescribed. Do not give ZIOPTAN® to other people, even if they
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`have the same symptoms that you have. It may harm them.
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`This Patient Information leaflet summarizes the most important information about ZIOPTAN®. If you would like more
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`information, talk with your doctor. You can ask your pharmacist or doctor for information about ZIOPTAN® that is written
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`What are the ingredients in ZIOPTAN®?
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`Active ingredients: tafluprost
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`Inactive ingredients: glycerol, sodium dihydrogen phosphate dihydrate, disodium edetate, and polysorbate 80,
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`hydrochloric acid and/or sodium hydroxide, and water
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`Instructions for Use
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`Read these Instructions for Use before using your ZIOPTAN® and each time you get a refill. There may be new
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`information. This leaflet does not take the place of talking with your doctor about your medical condition or your treatment.
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`Important:
` ZIOPTAN® is for the eye only. Do not swallow ZIOPTAN®.
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` ZIOPTAN® single-use containers are packaged in a foil pouch.
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` Do not use the ZIOPTAN® single-use containers if the foil pouch is opened.
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` Write down the date you open the foil pouch in the space provided on the pouch.
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`Every time you use ZIOPTAN:
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` Step 1. Wash your hands.
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` Step 2. Take the strip of single-use containers
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` Step 3. Pull off one single-use container from the
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` Step 4. Put
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` the remaining strip of single-use
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` the edge to close the pouch.
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`Reference ID: 3814364
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`14
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` Step 5. Hold
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` the single-use container upright.
` Make sure that your ZIOPTAN® medicine
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`is in the bottom part of the single-use
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`container.
`See Figure A.
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` Step 6. Open the single-use container by twisting
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` See Figure B.
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` Step 7. Tilt your head backwards. If you are
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` unable to tilt your head, lie down.
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` Step 8. Place the tip of the single-use container
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` close to your eye. Be careful not to touch
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` your eye with the tip of the single-use
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`container.
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` See Figure C.
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` Step 9. Pull your lower eyelid downwards and look
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` Step 10. Gently squeeze the container and let 1
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` drop of ZIOPTAN® fall into the space
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`between your lower eyelid and your eye. If
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`a drop misses your eye, try again.
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`See Figure D.
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` Figure A
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` Figure B
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` Figure C
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` Figure D
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` If your doctor has told you to use ZIOPTAN® drops in both eyes, repeat Steps 7 to 10 for your other eye.
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` The