IPR Page 1/11
`
`Santen/Asahi Glass Exhibit 2055
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`
`
`
`
`Exhibit 1
`Exhibit 1
`
`
`
`IPR Page 2/1 1
`
`IPR Page 2/11
`
`

`

`Japan Standard Product
`Classification No.
`871319
`
`Tapros Mini
`Ophthalmic solution
`0.0015%
`
`22500AMX00003000
`
`Tapros
`Ophthalmic solution
`0.0015%
`
`22000AMX02366000
`
`Dec 2008
`
`Dec 2008
`
`May 2013
`
`Dec 2013
`
`April 2008
`
`
`
`
`
`Approval
`no.
`NHI price
`listing
`On sale
`from
`
`International
`birth date
`
`
`
`[barcode]
`
`[barcode]
`
`**June 2017 Revision (9th ver., precautions revised)
`* February 2017 Revision
` Derivative
`Prostaglandin F2α
`Glaucoma and Ocular Hypertension Treatment
`
`Powerful drug, prescription drug (CAUTION—Use only by prescription from physician, etc.)
`TAPROS® ophthalmic solution 0.0015%
`Powerful drug, prescription drug (CAUTION—Use only by prescription from physician, etc.)
`TAPROS® Mini ophthalmic solution 0.0015%
`TAPROS® ophthalmic solution 0.0015%
`TAPROS® Mini ophthalmic solution 0.0015%
`Tafluprost ophthalmic solution
`
`Tapros Mini ophthalmic solution 0.0015%
`Tapros ophthalmic solution 0.0015%
`Storage: airtight container, room temperature Storage: airtight container, shade, 2-8°C
`Expiration date: on box and label (3 years) Expiration date: on box, foil pouches, and container (3 years)
`
`
`
`
`Warning: See handling precautions
`
`CONTRAINDICATIONS (not to be administered to the following patients)
`Patients with a history of sensitivity to the ingredients in the drug.
`
`COMPOSITION/PROPERTIES
`Trade Name
`Tapros ophthalmic
`solution 0.0015%
`
`Tapros Mini
`ophthalmic solution
`0.0015%
`
`Active ingredient
`Content (in 1 mL)
`Additives
`
`pH
`Osmotic pressure
`ratio
`Properties
`
`Tafluprost
`15 μg
`
`Polysorbate 80,
`concentrated glycerin,
`disodium edetate
`hydrate, sodium
`dihydrogen phosphate,
`benzalkonium chloride,
`pH modifier
`
`Polysorbate 80,
`concentrated glycerin,
`disodium edetate
`hydrate, sodium
`dihydrogen phosphate,
`pH modifier
`
`5.7–6.3
`
`1.0–1.1
`
`0.9–1.1
`
`Colorless, transparent, sterile aqueous eye drop
`
`
`
`
`[EFFICACY/EFFECTIVENESS]
`Glaucoma, ocular hypertension
`
`[DOSAGE METHOD/AMOUNT]
`One drop per eye per day.
`
`<DOSAGE METHOD/AMOUNT PRECAUTIONS>
`The effect of lowering the intraocular pressure might diminish if administered
`too frequently, so do not use more than once per day.
`
`*[PRECAUTIONS FOR USE]
`1. Careful Administration (use care when administering to the following
`patients)
`1) Patients suffering from aphakia or having intraocular insertion lenses [there
`are reports of the drug causing macular edema including cystoid macular edema,
`as well as low vision caused thereby.]
`2) Patients currently suffering from or with a history of bronchial asthma [there
`is a risk of aggravating or inducing asthma attacks.]
`3) Patients with endophthalmitis (iritis, uveitis) [there are reports of similar drugs
`causing an increase in intraocular pressure.]
`4) Women who are pregnant, giving birth, or nursing, etc. [See the
`“Administration to Women who are Pregnant, Giving Birth, or Nursing, etc.”
`section.]
`
`2. Important Basic Warnings
`1) Administration of this drug sometimes causes discoloration due to pigment
`deposits (increases in melanin) in the iris or the eyelid or increases in hair around
`the eye. These effects progress gradually as the drug is administered but stop
`when administration stops. Discoloration of the eyelids and increased hair
`therearound might disappear or diminish gradually after administration is
`stopped, but there are reports of the discoloration of the iris not disappearing
`after administration is stopped. The discoloration of the iris is clearly notable in
`patients with mixed-color irises but is also notable in patients with dark single-
`
`
`colored irises (common among Japanese people). There is a possibility
`of a difference between the hues of the irises in the left and right eyes,
`particularly in cases where the drug is administered only to one eye.
`There is insufficient long-term data on these symptoms, so it is
`important
`to see
`the patient regularly for observation. When
`administering the drug, fully brief patients on these symptoms and
`instruct them to wipe their eyelids and wash their faces thoroughly if any
`of the solution gets on the skin of the eyelids, etc., during administration,
`in order to prevent or minimize discoloration of the eyelid and increased
`hair growth therearound.
`2) Corneal epithelial disorders can occur when this drug is administered (superficial
`punctate keratitis, filamentous keratitis, corneal erosion), so instruct patients to come in
`for examination immediately if they ever become aware of ongoing symptoms such as
`numbness, itchiness, eye pain, or the like.
`3) Caution is required when administering this drug to patients suffering from closed-
`angle glaucoma, since such use has never been attempted.
`4) Temporarily blurred or misty vision can occur after administration, so warn patients
`not to operate machinery or drive, etc., until such symptoms disappear.
`3. Side-Effects
`Results of Tapros ophthalmic solution 0.0015% containing benzalkonium chloride are
`as follows.
`At Approval
`Of the total 483 cases, side-effects (including abnormal variation of clinical test values)
`were found in 326 (67.5%). The main side-effects were conjunctival hyperemia (151,
`31.3%), problems with eyelashes (93, 19.3%), itchiness (85, 17.6%), sensation of
`stimulation of the eye (65, 13.5%), and pigmentation of the iris (8.1%).
`
`
`(1)
`
`IPR Page 3/11
`
`

`

`2) Avoid administering the drug to nursing mothers, but if it is necessary, make the
`mother stop the nursing. [Transmission to the milk has been reported in animal testing
`(rats: eyedrop administration).]
`6. Administration to Children, etc.
`The safety of administration to low-birth-weight children, newborns, nursing children,
`infants, and toddlers has not been established (no data).
`7. Caution in Application
`1) Administration path: only use as eyedrops.
`2) When administering:
`Instruct patients to take care with the following.
`(1) To prevent contamination of the drug solution, do not allow the tip of the container
`to come in direct contact with the eye during administration.
`(2) If the solution gets on the eyelid skin, etc., wipe off immediately and wash your face.
`(3) When used in conjunction with other eyedrops, space administration at least five
`minutes apart.
`(4) Benzalkonium chloride can discolor contact lenses, so if this drug is administered
`when wearing contacts, remove the contacts, apply the drug, and then reinsert the
`contacts no sooner than 15 minutes later.
`(Tapros ophthalmic solution 0.0015% only)
`(5) During use, discard the first one or two drops (to remove any pieces of the container
`after opening).
`(Tapros Mini ophthalmic solution 0.0015% only)
`(6) Discard any unused solution, since it is a single-use sterile disposable solution which
`contains no preservatives to prevent secondary contamination.
`(Tapros Mini ophthalmic solution 0.0015% only)
`
`How to Administer Tapros Mini Ophthalmic Solution 0.0015%
`
`Remove a single container.
`
`Discard one to two drops
`prior to application to eye.
`
`As shown in the figure, grip
`the part containing no solution
`and twist the tip of the
`container to remove it.
`
`Insert the drops without
`letting the container come in
`contact with the eye.
`
`
`
`
`
`Investigation of Specific Use Results (5th Regular Safety Report)
`Of the total 3,260 cases, side-effects were found in 396 (12.1%). The main side-
`effects were pigmentation of the eyelid (93, 2.9%), conjunctival hyperemia (74,
`2.3%), corneal erosion and other corneal epithelial disorders (58, 1.8%),
`excessive hair growth on the eyelids (40, 1.2%), and problems with the eyelashes
`(39, 1.2%).
`1) Serious Side-Effects
`Pigmentation of the iris (8.1%): Pigmentation of the iris can occur, so patients
`need to be seen regularly, and administration should be stopped depending on the
`clinical state if such pigmentation occurs.
`2) Other Side-Effects
`Take appropriate steps, including halting administration, if other side-effects
`occur.
`Freq
`
`Unknown freq.
`
`5% or more
`
`1-5% 0.1-1%
`
`Type
`
`Eye
`
`Sub-
`conjunctival
`hemorrhage
`
`Conjunctivitis,
`iritis, kerato-
`conjunctivitis
`sicca,
`deepening of
`the
`suprapalpebral
`sulcus,
`macular
`edema
`
`Conjunctival hyperemia,
`problems with the eyelashes
`(lengthening, thickening of
`eyelashes or increase in
`number, etc.) itchiness, sense
`of stimulation, feeling of
`something in eye, eyelid
`pigmentation, superficial
`punctate keratitis and other
`corneal epithelial disorders,
`discomfort in the eyes (strange
`feeling, stickiness, dryness,
`etc.)
`
`Eye pain,
`increased hair on
`eyelid,
`discharge,
`photophobia,
`heavy feeling,
`tearing, blurred
`vision, macular
`edema, swelling
`of the eyelid
`(redness of the
`eyelid, edema,
`etc.)
`
`Neuro-
`psychiatric
`
`Sensitivity
`
`—
`
`Eyelid
`swelling
`
`—
`
`—
`
`Headache
`
`Dizziness
`
`Erythema —
`
`AST (GOT)
`increase,
`positive urinary
`protein, serum
`potassium
`increase
`
`Other
`
`
`
`
`
`ALT (GPT)
`increase, γ-
`GTP increase,
`positive
`urinary sugar,
`increase in
`acidophilic
`leukocytes,
`reduction in
`white blood
`cell count, uric
`acid increase
`Frequency of presentation was calculated on the basis of clinical trial results up
`to approval of Tapros ophthalmic solution 0.0015% containing benzalkonium
`chloride.
`4. Administration to the Elderly
`Use caution, since physiological functions are generally lowered in the elderly.
`5. Administration to Women who are Pregnant, Giving Birth, or Nursing,
`etc.
`1) Only administer this drug to women who are or might be pregnant in cases
`where the therapeutic benefit is deemed to outweigh the risks. [The safety of
`administration during pregnancy has not been established. In animal trials, there
`was an increase in teratogenicity and post-implantation losses after intravenous
`administration of 30 μg/kg/day (2000 times the clinical dosage) to pregnant rats,
`
`and growth of fetuses was affected (low fetal weight and unossifsication of the
`sternum) at 10 μg/kg/day (approx. 670 times the clinical dosage). An increase in
`miscarriages, post-implantation losses, lower luteal bodies, and smaller litters
`were seen after intravenous administration of 0.1 μg/kg/day (approx. 6.7 times
`the clinical dosage) to pregnant rabbits, and teratogenicity was found at 0.03
`μg/kg/day (twice the clinical dosage). Intravenous administration of 1 μg/kg/day
`(approx. 67 times the clinical dosage) resulted in problems with nursing and a
`lowering of the day four survival rate of offspring. In tests using extracted rat
`uteri, shrinkage of the uterus was seen at approx. 3.3 times the estimated plasma
`concentration (less than 30 pg/mL) during administration of the clinical dosage*
`as eye drops, or approx. 420 times the estimated plasma unbound drug
`concentration when converted using the protein binding ratio (less than 0.24
`pg/mL).
`*The dosage (0.015 μg/kg/day) when a 0.0015% solution of the drug is
`administered to each eye as one drop (30 μL) per day to a patient weighing 60 kg.
`
`(2)
`
`IPR Page 4/11
`
`

`

`All cases
`Hypertension
`Hypotension
`
`pressure
`
`Change in intraocular
`
`Time
`
`(All cases)
`(Hypertension)
`(Hypotension)
`(Weeks)
`
`
`Average ± standard dev.
`
`[PHARMACOLOGY]
`1. Effect of Lowering Intraocular Pressure6)
`When 0.00002% to 0.005% Tafluprost ophthalmic solution was administered as a single eye
`drop to monkeys, a concentration-dependent drop in intraocular pressure effect was found
`which was significant relative to the base drug group at a concentration of 0.0005% or above.
`When 0.001% to 0.005% Tafluprost ophthalmic solution was administered to monkeys once a
`day for five days, the drop in intraocular pressure continued stably over the entire period at all
`dosages, without any weakening of the effect.
`2. Mechanism of Action6)
`Tafluprost carboxylic acid, the active metabolite, displayed affinity (Ki = 0.40 nM) to
`prostanoid FP receptors. Monkeys were given one dose per day of 0.005% Tafluprost
`ophthalmic solution for three to five days, and the aqueous humor dynamics were measured
`using fluorophotometry, two-level constant perfusion, 125I–131I-labeled albumin perfusion. No
`changes were seen in aqueous humor production, and there was a significant increase in the
`uvea sclera flow.
`3. Effect on Ocular Blood Flow
`1) Tapros ophthalmic solution 0.0015% was administered once a day for 28 days to rabbits,
`and when measurements were done using a laser speckle method, a significant increase was
`seen in the blood flow in the papillary tissue of the optic nerve.7)
`2) When healthy adults were given a single dose of Tapros ophthalmic solution, significant
`increases were seen in the blood flow velocity in the perioptic papillary retinal artery and the
`tissue of the perioptic papillary retina.8)
`
`[PHYSICOCHEMICAL FINDINGS ON THE ACTIVE INGREDIENT]
`Common 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
`Chemical structure:
`
`
`
`
`Molecular formula: C25H34F2O5
`Molecular weight: 452.53
`Properties: Colorless to light-yellow viscous liquid. Dissolves in ethanol, diethylether, and
`acetonitrile, but is practically insoluble in water.
`
`
`(3)
`
`
`
`[PHARMACOKINETICS]
`1. Plasma concentration1)
`When one drop per day was administered for seven days to seven healthy
`adults each in a 0.0025% or 0.005% Tafluprost ophthalmic solution group,
`the plasma concentration of Tafluprost or Tafluprost carboxylic acid which
`is the active metabolite was detected as 0.144 ng/mL of Tafluprost
`carboxylic acid after 15 min after administration on the first day in one case
`in the 0.0025% group, but aside from that all measurements were below the
`lower limits (Tafluprost: 0.2 ng/mL, Tafluprost carboxylic acid: 0.1 ng/mL).
`Note: the concentration of the drug is 0.0015%.
`2. Transmission in Animal Eye Tissue2)
`(Reference: monkey)
`When a single dose of 0.005%3 H-Tafluprost ophthalmic solution was
`administered to a monkey, radiation distributed rapidly throughout the eye
`tissue, the maximum radiation concentration was seen in the cornea and
`conjunctiva 5–15 min after administration, and
`two hours after
`administration in the aqueous humor, the ciliary body, and the crystalline
`lens, after which it rapidly disappeared.
`
`[CLINICAL RESULTS]
`1. In a randomized blind study of 109 patients suffering from primary open-
`angle glaucoma or ocular hypertension (control drug: Latanoprost
`ophthalmic solution), there was a 6.6 mmHg drop in intraocular pressure
`with Tapros ophthalmic solution 0.0015% (5.8–7.3 mmHg in the 95%
`confidence interval), verifying noninferiority relative to the control drug.3)
`Comparison of Intraocular Pressure (mmHg)
`Tapros ophthalmic
`solution 0.0015%
`(n=46)
`23.8 ± 2.3
`
`
`
`Baseline
`After treatment period
`(after four weeks or when ended)
`Change in intraocular pressure
`Group difference in average
`(Tapros ophthalmic solution
`0.0015% – control drug)
`95% confidence interval for
`difference in averages
`
`Control drug
`(n=51)
`
`23.7 ± 2.3
`
`17.2 ± 2.8
`
`–6.6 ± 2.5
`
`17.5 ± 2.7
`
`–6.2 ± 2.5
`
`–0.41
`
`–1.42 to 0.60
`
`(Average ± standard dev.)
`Noninferiority limit: 2 mmHg
`2. In a randomized blind study of 94 patients suffering from normal tension
`glaucoma (control drug: placebo ophthalmic solution), there was a 4.0
`mmHg drop in intraocular pressure with Tapros ophthalmic solution
`0.0015% (3.5–4.5 mmHg in the 95% confidence interval), demonstrating a
`significant drop in intraocular pressure compared to the control drug.4)
`Comparison of Intraocular Pressure (mmHg)
`Tapros ophthalmic
`solution 0.0015%
`(n=46)
`23.8 ± 2.3
`
`
`
`Baseline
`After treatment period
`(after four weeks or when
`ended)
`Change in intraocular
`pressure
`Group difference in average
`(Tapros ophthalmic solution
`0.0015% – control drug)
`95% confidence interval for
`difference in averages
`
`Control drug
`(n=51)
`
`23.7 ± 2.3
`
`17.2 ± 2.8
`
`17.5 ± 2.7
`
`–6.6 ± 2.5
`
`–6.2 ± 2.5
`
`–0.41
`
`–1.42 to 0.60
`
`(Average ± standard dev.)
`Noninferiority limit: 2 mmHg
`3. In a long-term trial of 351 patients suffering from elevated intraocular
`pressure or open-angle glaucoma, including normal tension glaucoma, the
`drop in intraocular pressure from Tapros ophthalmic solution 0.0015% was
`
`4.9–5.7 mmHg for 52 weeks, and the effect of lowering the intraocular
`pressure was maintained stably in all long-term cases. Of these, the drop in
`intraocular pressure in the ocular hypertension group* was 6.0–6.9 mmHg
`for 52 weeks, and 3.4–4.0 mmHg in the hypotension group*.5)
`*The hypertension group had a baseline intraocular pressure of 22–34
`mmHg and the hypotension group had one of 16–21 mmHg.
`
`IPR Page 5/11
`
`

`

`
`
`
`**[PRECAUTIONS FOR USE]
`
`After opening the foil pouches, store the containers in the included light-
`
`shielding bags at 2–8°C, and use within one year. Use within one month if stored
`at room temperature.
`
`
`Use the product starting from the container whose foil pouch has been opened
`first.
`
`(Tapros Mini ophthalmic solution 0.0015% only)
`
`
`
`
`[WRAPPING]
`Tapros ophthalmic solution 0.0015%:
`
`Plastic solution containers
`5 × 2.5 mL
`
`
`
`
`10 × 2.5 mL
`
`Tapros Mini ophthalmic solution 0.0015%:
`
`Plastic solution containers
`30 × 0.3 mL
`
`
`
`
`(3 bags of 10 containers in
`
`
`foil pouches)
`
`
`
`
`[PRECAUTIONS REGARDING INSURANCE]
`
`Insurance payouts are calculated for Tapros Mini ophthalmic solution 0.0015%
`only when used by the following patients.
`
`(1) Patients who are or might be sensitive to benzalkonium chloride.
`
`(2) Patients suffering from corneal epithelial disorders.
`
`
`
`
`[CITATIONS AND CITATION REQUESTS]
`
`<Citations>
`
`1) Safety,
`tolerability, pharmacokinetics and pharmacodynamics of AFP-168
`(0.0025 ％ and 0.005%) eye drops after dosing for one week. A phase I, active-
`
`
`and placebo-controlled parallel study in healthy Japanese male volunteers,
`
`Santen Pharmaceutical Co., Ltd. internal document
`[60765]
`
`2) Fukano Y. et al.: J. Ocul. Pharmacol. Ther. 27, 251 (2011)
`
`
`
`3) Kuwayama Y. et al: New Ophthalmology 25, 1595 (2008)
`
`[60767]
`
`
`4) Kuwayama Y. et al: Journal of the Japanese Ophthalmological Society 114,
`
`436 (2010)
`[60768]
`
`5) 0.015% DE-085 Tenganeki No Kaiho Gukaku Ryokunaisho Matawa
`
`Koganatsusho O Taisho Toshita Opun Raberu Ni Yoru Choki Tengan Shiken–
`
`Dai III So–, Santen Pharmaceutical Co., Ltd. internal document[60769]
`
`6) Takagi Y. et al.: Exp. Eye Res. 78, 767 (2004)
`
`
`
`7) Akaishi T. et al.: J. Ocul. Pharmacol. Ther. 26, 181 (2010)
`
`[60770]
`
`
`8) 0.0015% DE-85 (Tafluprost) Tenganeki No Kenko Seijin Dansei O Taisho
`
`Toshita Rinshou Yakuri Shiken–Gan Ketsuryu Dotai O Shihyo Toshita Kento–,
`
`Santen Pharmaceutical Co., Ltd. internal document
`[60771]
`
`
`
`CITATION REQUESTS AND PRODUCT INQUIRIES
`
`Please direct any requests for the internal documents listed in the citations to the
`
`following location.
`
`Medical Drug Data Office, Medical Drug Division, Santen Pharmaceutical Co.,
`
`Ltd.
`
`3-9-19 Shimo Shinjo, Higashi Yodogawa-ku, Osaka-shi 533-8651 (individual
`
`postal code)
`
`Tel: 0120-921-839 06-6321-7056
`
`Hours: 9:00 am to 5:00 pm (closed weekends and holidays)
`
`
`
`
`
`
`
`
`
`
`
`[60766]
`
`[60134]
`
`Made by: Santen Pharmaceutical Co., Ltd.
`4–20 Ofuka-cho, Kita-ku, Osaka-shi
`
`
`16
`
`30402
`
`(4)
`
`IPR Page 6/11
`
`

`

`
`
`
`
`Exhibit 2
`Exhibit 2
`
`
`
`IPR Page 7/1 1
`
`IPR Page 7/11
`
`

`

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`„
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`IPR Page 8/11
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`

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`IPR Page 9/11
`
`

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