Tapcom

Tafluprost, timolol.

Content (per mL) of active ingredient: Tafluprost 15 µg, Timolol maleate 6.83 mg (equivalent to 5 mg Timolol).
pH: 6.7-7.2.
Osmolar Ratio: 1.0-1.1.
Excipients/Inactive Ingredients: Polysorbate 80, concentrated glycerin, disodium edetate hydrate, sodium dihydrogen phosphate dihydrate, benzalkonium chloride and pH adjuster.

Pharmacology: Pharmacodynamics: Intraocular pressure (IOP) lowering effect: Ocular administration of this product in a single dose to monkeys showed statistically significant IOP lowering effect. The effect was significantly greater than that of monotherapy containing individual active ingredients (i.e. 0.0015% tafluprost ophthalmic solution and 0.5% timolol ophthalmic solution).
Mechanism of action: Tafluprost carbonic acid, an active form of tafluprost, is an agonist to prostanoid FP receptor, and timolol maleate is a non-selective blocker to β adrenaline receptor. These active ingredients of this product lower IOP by the different modes of action.
Tafluprost acid form, an active metabolite of tafluprost, showed high affinity for the prostanoid FP receptor (Ki=0.40 nM). Aqueous humor dynamics in monkeys was evaluated using fluorophotometry, two-level constant pressure perfusion and ¹²⁵I-¹³¹I labeled albumin perfusion methods following the repeated administration of 0.005% tafluprost ophthalmic solution once daily for 3 to 5 days. Uveoscleral outflow was significantly increased without any change in aqueous production.
Mechanism of action of timolol maleate is not clear but it was suggested that the effect is caused mainly by decreasing aqueous production, which was demonstrated by the fluorophotometry study in monkeys and healthy subjects and the tonography test in glaucoma patients.
Effect on ocular blood flow: A repeated instillation of tafluprost ophthalmic solution 0.0015% into rabbit eyes once daily for 28 days significantly increased the blood flow in the optic nerve head, measured with laser speckle method.
A single dose instillation of tafluprost ophthalmic solution 0.0015% into eyes of healthy adults significantly increased the blood flow rate in the paraoptic nerve head retinal artery and the tissue blood flow at the paraoptic nerve head retina.
Clinical efficacy: In a randomized masked comparison study in 487 patients with primary open angle glaucoma or ocular hypertension, using Tafluprost ophthalmic solution 0.0015% (once daily) (here after Tafluprost group) or concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily) (here after Concomitant group) as a comparator, after instillation of Tafluprost ophthalmic solution 0.0015% (once daily) during 4 weeks of run-in period and instillation of TAPCOM (once daily) or each control drug in a double-masked manner during 4 weeks of treatment period, the superiority of TAPCOM to Tafluprost group (p<0.001) and the non-inferiority to Concomitant group was confirmed (ANCOVA with baseline IOP as covariate). TAPCOM was confirmed to be non-inferior to Concomitant group in IOP lowering (Table 1 and Figure 1). (See Table 1 and Figure 1.)


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In a randomized masked comparison study in 166 patients with primary open angle glaucoma or ocular hypertension using Timolol ophthalmic solution 0.5% (twice daily) (here after Timolol group) as a comparator, after instillation of Timolol ophthalmic solution 0.5% (twice daily) during 4 weeks of run-in period and instillation of TAPCOM (once daily) or control drug in a double-masked manner during 4 weeks of treatment period, the superiority of TAPCOM to Timolol group was confirmed (p<0.001) (ANCOVA with baseline IOP as covariate) (Table 2 and Figure 2). (See Table 2 and Figure 2.)


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In a long-term administration study in 136 patients with primary open angle glaucoma including normal tension glaucoma or ocular hypertension, TAPCOM was instilled during 52 weeks of treatment period following 4 weeks of run-in period with using Tafluprost ophthalmic solution 0.0015% (once daily), Timolol ophthalmic solution 0.5% (twice daily), or concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily). In case of switching from Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily), the IOP change from baseline (Week 0) was statistically significant at all measurement points (p<0.001). In case of switching from concomitant Tafluprost ophthalmic solution 0.0015% (once daily) and Timolol ophthalmic solution 0.5% (twice daily), no significant change in IOP was observed throughout the treatment period compared with baseline (Week 0), and the time course of IOP remained stable during the 52 weeks(Figure 3). (See Figure 3.)


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Pharmacokinetics: Plasma concentrations: One drop of TAPCOM ophthalmic solution (once daily), 0.0015% tafluprost ophthalmic solution (once daily), 0.5% timolol ophthalmic solution (twice daily) and a combination of 0.0015% tafluprost ophthalmic solution (once daily)/0.5% timolol ophthalmic solution (twice daily) were instilled to both eyes of 32 healthy adult volunteers for 7 days and plasma concentrations of timolol and tafluprost acid which is an active metabolite of tafluprost were measured.
The C_max of tafluprost acid on the first and seventh day in the repeated instillation of TAPCOM were similar levels to that with the single use of tafluprost and the combination of tafluprost/timolol. The C_max and AUC_inf of timolol on the first and seventh day in the repeated instillation of TAPCOM were similar levels to that with the single use of timolol and the combination of tafluprost/timolol. (See Table 3.)


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Ocular tissue distribution in animals (for reference : Rats): The concentration profiles of tafluprost acid and timolol in aqueous humor following a single ocular instillation of TAPCOM ophthalmic solution to rats were similar to those in combination with a single ocular instillation of 0.5% timolol ophthalmic solution and 0.0015% tafluprost ophthalmic solution with 5-minute interval.

Reduction of Intraocular pressure (IOP) in adult patients with open angle glaucoma or ocular hypertension who are insufficiently responsive to topical monotherapy with beta-blockers or prostaglandin analogues and require a combination therapy.

Instill 1 drop in the affected eye(s) once daily.
SPECIAL POPULATION: Pediatric Population: The safety and efficacy of TAPCOM in children and adolescents below the age of 18 years have not been established. No data are available. TAPCOM is not recommended for use in children and adolescents below the age of 18years.
Use in Renal/Hepatic Impairment: Tafluprost and timolol ophthalmic solutions have not been studied in patients with renal/hepatic impairment and TAPCOM should therefore be used with caution in such patients.

No particulars.
Treatment of overdose: No particulars.

Patients with bronchial asthma or a history of bronchial asthma, bronchospasm, or severe chronic obstructive pulmonary disease [Asthmatic attack may be aggravated or induced due to bronchial smooth muscle contraction caused by β-receptor blockage.].
Patients with poor-controlled cardiac failure, sinus bradycardia, second-or third-degree atrioventricular block, or cardiogenic shock [These symptoms may be aggravated due to negative chronotropic/inotropic effects caused by β-receptor blockage.].
Patients with a history of hypersensitivity to any of the ingredients in this product.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since this drug contains benzalkonium chloride, close monitoring is required with frequent or prolonged use in dry eye patients, or in conditions where the cornea is compromised.
Contact lenses: Patients should be advised not to wear a contact lens if their eye is red. This drug should not be used to treat contact lens related irritation. The preservative in this drug, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red should be instructed to wait at least 15 minutes after instilling this drug before they insert their contact lenses.

Careful administration (This product should be administered with care to the following patients.): Patients with right ventricular failure caused by pulmonary hypertension [Symptoms may be aggravated due to negative chronotropic/inotropic effects caused by β-receptor blockage.].
Patients with congestive heart failure [Symptoms may be aggravated due to negative chronotropic/inotropic effects caused by β-receptor blockage.].
Patients with diabetic ketoacidosis or metabolic acidosis [This product may enhance the depression of myocardial contraction caused by acidosis].
Patients with poor-controlled diabetes [Pay attention to the blood glucose level because this product may mask hypoglycemia.].
Patients with aphakia or pseudophakia [Other drugs in this category have been reported to induce macular oedema including cystoid macular oedema, and associated visual acuity reduction.].
Patients with intraocular inflammation (iritis, uveitis) [Other drugs in this category have been reported to cause elevation of intraocular pressure.].
Pregnant, parturient and lactating women [See Use in Pregnancy & Lactation].
Important precautions: This product is a combination ophthalmic solution containing 15 µg/mL of tafluprost and 6.83 mg/mL of timolol maleate equivalent to timolol 5 mg/mL. Use this product appropriately because adverse drug reactions may be induced by both of the previously mentioned active ingredients.
This product may be absorbed systemically, and cause adverse drug reactions similar to those caused by systemic administration of a β-blocker.
Pigmentation in iris and eyelid (increased melanin content), or hypertrichosis around the eyes may occur. These symptoms gradually progress with continued administration, and stop when treatment is discontinued. Symptoms like blepharal pigmentation and hypertrichosis around the eyes can gradually disappear or diminish after administration is discontinued, however, there are reports that iris pigmentation persisted even after administration was discontinued. In such cases, iris color change can be detected clearly in patients with mixed-color irises and even in patients with single-color dark brown irises (seen among most Japanese) as well. The difference in iris color between right and left eyes could be noted particularly in the case of unilateral administration. As long-term observation data about these symptoms are not yet available, doctors are required to closely observe patients through periodic checkups. Patients should be well informed of the possibility of these symptoms and instructed to wipe off any excess solution from the skin around the eye or to wash their faces in order to prevent blepharal pigmentation or hypertrichosis around eyes.
Corneal epithelium disorder (superficial punctate keratitis, filamentary keratitis or corneal erosion) may occur during treatment. Instruct patients to consult a doctor immediately if symptoms including eye stinging, itching, and eye pain continue.
This product should be administered carefully, because there is no clinical experience in patients with closed angle glaucoma.
Pay close attention when medication is switched from a miotic to this product. This is because the switch from a miotic to timolol maleate may require refraction adjustment due to loss of miotic action.
Precautions concerning use: Priority should be given to monotherapy in principle.
Do not use more than once daily because more frequent administration may lessen the intraocular pressure (IOP) lowering effect.
Route of administration: Ophthalmic use only.
At the time of administration: The following instructions should be given to patients: Be careful not to touch the tip of the bottle to the eye directly in order to avoid contamination of the drug.
In principle, lie supine, the eyelids apart and instill the product into the conjunctival sac, then close the eye and press the lacrimal sac for 1-5 minutes.
Wipe off or wash the face immediately when any excess solution touches the skin around the eye.
When more than one ophthalmic drug is used, at least 5 minutes of intervals should be taken.
Contact lenses should be removed prior to administration because benzalkonium chloride may care discoloration of the lenses. Wait at least 15 minutes before wearing the contact lenses again.
Effects on ability to drive and use machine: Temporary blurred vision may develop after administration of this product. Instruct patients to refrain from activities including driving or operating machinery until the symptom disappears.
Use in Children: The safety of this product in low-birth-weight infants, neonates, infants or children has not been established. (No clinical experience.).
Use in the Elderly: Because physiological function is generally reduced in the elderly, caution should be exercised.

This product should be used for pregnant women or women who may possibly be pregnant only if the expected therapeutic benefits are judged to outweigh the possible risks associated with the treatment. [The safety of this product for use during pregnancy has not been established. In animal studies, when tafluprost solution was administered intravenously to pregnant rats at a dose of 30 µg/kg/day (2000 times the clinical dose^*), teratogenicity and post-implantation embryonic mortality rate increased; at 10 µg/kg/day (about 670 times the clinical dose^*) adverse effects on fetal development (low body weight and unossification of breast bone in fetuses) was observed. In intravenous administration in pregnant rabbits at 0.1 µg/kg/day (about 6.7 times the clinical dose^*), the miscarriage and mortality rate after implantation increased, and luteal body and implantation decreased; at 0.03 µg/kg/day (2 times the clinical dose^*) teratogenicity was observed. In an intravenous administration study in pregnant and lactating rats at a dose level of 1 µg/kg/day (about 67 times the clinical dose^*), mal-nursing of dams was observed and the 4-day survival rate of new born baby decreased. On the other hand, in the study using uteri isolated from rats, uterine contraction was observed at about 3.3 times the plasma concentration of tafluprost (less than 30 pg/mL), or about 420 times the plasma concentration of unbound tafluprost (less than 0.24 pg/mL), calculated based on the protein binding ratio, estimated after ocular administration of the clinical dosage.].
^*Dosage (0.015 µg/kg/day) when one drop (30 µL) of tafluprost ophthalmic solution 0.0015% is instilled into both eyes at a time for a 60 kg patient.
Avoid administration to nursing mothers. If administration is judged to be essential, the patients should be instructed to stop breast-feeding during treatment. [A study has shown excretion of tafluprost in breast milk after ocular instillation in rats. Timolol maleate may be excreted in human breast milk.].
(Additional information): In animal studies, delayed ossification in the fetuses was observed when timolol maleate was administered orally to pregnant rats during organogenesis at a dose of 500 mg/kg/day. Increased fetal death was observed when timolol maleate was administered orally to mice at a dose of 1000 mg/kg/day and to rabbits at a dose of 200 mg/kg/day.

Adverse drug reactions (including abnormal change in laboratory test values) were reported in 94 of 379 patients (24.8%) in clinical studies in Japan. The major adverse drug reactions were abnormality in eyelashes in 35 patients (9.2%), conjunctival injection in 32 patients (8.4%), corneal epithelium disorder including punctate keratitis in 21 patients (5.5%), blepharal pigmentation in 9 patients (2.4%), eye irritation in 8 patients (2.1%), etc. (At the time of approval).
Clinically significant adverse drug reactions: Iris pigmentation (incidence unknown)^*: Iris pigmentation may occur. Patients should be examined periodically, and administration should be discontinued depending on clinical status when iris pigmentation is observed.
Ocular pemphigoid (incidence unknown)^*: Ocular pemphigoid may occur. Discontinue administration and treat the patient appropriately when symptoms including conjunctival injection, corneal epithelium disorder, keratoconjunctivitis sicca, conjunctival atrophy, ciliary entropion or symblepharon are observed.
Bronchospasm, dyspnea, respiratory failure (incidence unknown)^*: Bronchospasm, dyspnea or respiratory failure may occur. Discontinue administration and treat the patient appropriately if such symptoms are observed.
Heart block, congestive heart failure, cerebral ischemia, cardiac arrest, cerebrovascular disorder (incidence unknown)^*: Heart block, congestive heart failure, cerebral ischemia, cardiac arrest or cerebrovascular disorder may occur. Discontinue administration and treat the patient appropriately if such symptoms are observed.
Systemic lupus erythematosus (incidence unknown)^*: Systemic lupus erythematosus may occur. Discontinue administration and treat the patient appropriately if such symptom is observed.
^*: Adverse drug reactions which have been reported in use of tafluprost or timolol maleate.
Other adverse drug reactions: If an adverse drug reaction is observed, appropriate measures including discontinuing administration should be taken. (See Table 4.)


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Caution for concomitant use: Since this product contains timolol maleate, caution should be exercised in the concomitant use of the following drugs. (See Table 5.)


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Store in refrigerator (2°C to 8 °C) under protection from light.
Store below 30°C after opening and use within 1 month.
Shelf life: 36 months.

Antiglaucoma Preparations

S01ED51 - timolol, combinations ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.

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