Tapcom/Tapcom-S

Tafluprost, timolol maleate.

Tapcom: Each mL contains 15 μg of tafluprost and 6.83 mg of timolol maleate (equivalent to 5 mg of timolol). Its pH is 6.7-7.2 and its osmolar ratio is 1.0-1.1.
Tapcom-S: It has a pH of 6.0-6.7 and an osmolality of 290-370 mOsm/kg.
Excipients/Inactive Ingredients: Tapcom: Sodium dihydrogen phosphate dehydrate, polysorbate 80, disodium edetate hydrate, concentrated glycerin, benzalkonium chloride and pH adjuster as additives.

Pharmacotherapeutic Group: Antiglaucoma preparations and miotics, beta-blocking agents. ATC Code: S01ED51.
Pharmacology: Pharmacodynamics: Tapcom: 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.
Tapcom-S: TAPCOM-S is a fixed combination of two active substances tafluprost and timolol. These two active substances lower intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound alone.
Tafluprost is a fluorinated analogue of prostaglandin F_2α. Tafluprost acid, the biologically active metabolite of tafluprost, is a highly potent and selective agonist of the human prostanoid FP receptor. Pharmacodynamic studies in monkeys indicate that tafluprost reduces intraocular pressure by increasing the uveoscleral outflow of aqueous humour.
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent. The precise mechanism of action of timolol maleate in lowering intraocular pressure is not clearly established at this time, although a fluorescein study and tonography studies indicate that the predominant action may be related to reduced aqueous formation. However, in some studies a slight increase in outflow facility was also observed.
Tapcom: 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.
Tafluprost acid form, an active metabolite, 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 significantly increased without any change in aqueous production.
Effect on ocular blood flow: A repeated instillation of this product 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 this product into eyes of healthy adults significantly increased the blood flow rate in the paraoptic nerve head retinal artery and the blood flow at the paraoptic nerve head retina.
Clinical Studies: Tapcom: 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 (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 1OP as covariate) (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 form 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 (see Figure 3).

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Tapcom-S: In a 6-month study (n=400) in patients with open-angle glaucoma or ocular hypertension and mean untreated IOPs between 24-26 mmHg, the IOP lowering effect of TAPCOM-S (once daily in the morning) was compared to concomitant administration of 0.0015% tafluprost (once daily in the morning) and 0.5% timolol (twice daily). TAPCOM-S was non-inferior to the effect of concomitantly used 0.0015% tafluprost and 0.5% timolol at all time points and visits with the generally used non-inferiority margin of 1.5 mmHg. The mean diurnal IOP decrease from baseline was 8 mmHg in both arms at the primary endpoint of 6 months (decreases ranging between 7 to 9 mmHg in both arms at the different time points during the day over the study visits).
Another 6-month study (n=564) compared TAPCOM-S with the respective monotherapies in patients with open-angle glaucoma or ocular hypertension and mean untreated IOPs between 26-27 mmHg. Patients insufficiently controlled either with 0.0015% tafluprost (IOP 20 mmHg or greater on treatment) or 0.5% timolol (IOP 22 mmHg or greater on treatment) were randomized to be treated with TAPCOM-S or the same monotherapy. The mean diurnal IOP reduction of TAPCOM-S was statistically superior to that of tafluprost given once daily in the morning or timolol given twice daily, at visits 6 weeks, 3 months (primary efficacy endpoint) and 6 months. The mean diurnal IOP decrease from baseline of TAPCOM-S at 3 months was 9 mmHg, in comparison to 7 mmHg observed for both monotherapies. IOP decreases with TAPCOM-S at the different time points during the day over the visits ranged between 8 to 9 mmHg in the tafluprost monotherapy comparison group and between 7 to 9 mmHg in the timolol monotherapy comparison group.
Combined data from TAPCOM-S patients with high baseline IOP of 26 mmHg (mean diurnal) or above in these two pivotal studies (n=168) showed that the mean diurnal reduction in the IOP was 10 mmHg at the primary end point (3 or 6 months) ranging between 9 and 12 mmHg at the different time points during the day.
The European Medicines Agency has waived the obligation to submit the results of studies with TAPCOM-S in all subsets of the paediatric population.
Pharmacokinetics: Tapcom: This product is containing tafluprost and timolol maleate. Tafluprost is rapidly metabolized tafluprost acid which is an active form after ocular instillation.
Plasma concentrations: One drop of this product (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 this product 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 this product were similar levels to that with the single use of timolol and the combination of tafluprost/timolol.
Pharmacokinetic parameters in once-daily repeated instillation of this product for 7 days. (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 this product 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.
Biotransformation and elimination: Tafluprost acid, which is an active metabolite and rapidly generated by the hydrolysis of tafluprost following ocular instillation, is metabolized by -oxidation and then excreted into urine and bile, i.e. most of administered tafluprost is eliminated by metabolism. Timolol is absorbed after ocular instillation and metabolized by CYP2D6. Timolol is mainly excreted into urine but approximately 17% of dose is excreted as an unchanged form in urine.
Tapcom-S: Absorption: Plasma concentrations of tafluprost acid and timolol were investigated in healthy volunteers after single and repeated ocular dosing for eight days of TAPCOM-S (once daily), 0.0015% tafluprost (once daily) and 0.5% timolol (twice daily). Tafluprost acid plasma concentrations peaked at 10 minutes after dosing and declined below the lower limit of detection (10 pg/ml) before 30 minutes after TAPCOM-S dosing. Accumulation of tafluprost acid was negligible and the tafluprost acid mean AUC_0-last (monotherapy: 4.45±2.57 pg·h/ml; TAPCOM-S: 3.60±3.70 pg·h/ml) and the mean C_max (monotherapy: 23.9±11.8 pg/ml; TAPCOM-S: 18.7±11.9 pg/ml) were both slightly lower with TAPCOM-S as compared to tafluprost monotherapy on Day 8. Timolol plasma concentrations peaked at median T_max values of 15 and 37.5 minutes after TAPCOM-S dosing on Days 1 and 8, respectively. The Day 8 timolol mean AUC_0-last (monotherapy: 5750±2440 pg·h/ml; TAPCOM-S:4560±2980 pg·h/ml) and the mean C_max (monotherapy: 1100±550 pg/ml; TAPCOM-S: 840±520 pg/ ml) were both somewhat lower with TAPCOM-S compared to timolol monotherapy. The lower plasma timolol exposure with TAPCOM-S appears to be due to once-daily dosing for TAPCOM-S versus twice daily dosing with timolol monotherapy. Tafluprost and timolol are absorbed through the cornea. In rabbits, corneal penetration of tafluprost from TAPCOM-S was similar to that of tafluprost monopreparation after a single instillation while the penetration of timolol was slightly less from the TAPCOM-S compared to timolol monopreparation. For tafluprost acid, AUC_4h was 7.5 ng·h/ml following administration of TAPCOM-S and 7.7 ng·h/ml following administration of tafluprost monopreparation. For timolol, AUC_4h was 585 ng·h/ml and 737 ng·h/ml following administration of TAPCOM-S and timolol monopreparation, respectively. T_max for tafluprost acid was 60 minutes for both TAPCOM-S and tafluprost monopreparation, while for timolol T_max was 60 minutes for TAPCOM-S and 30 minutes for timolol monopreparation.
Distribution: Tafluprost: 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. In a whole body autoradiography study in rats, the highest concentration of radioactivity was observed in the cornea followed by the eyelids, sclera and the iris. Outside the eye radioactivity was distributed to the lacrimal apparatus, palate, oesophagus and gastrointestinal tract, kidney, liver, gall bladder and urinary bladder. The binding of tafluprost acid to human serum albumin in vitro was 99% at 500 ng/ml tafluprost acid.
Timolol: The peak level of timolol-related radioactivity in the aqueous humor was reached after 30 minutes following a single application of ³H-radiolabelled timolol (0.5% solution: 20 μl/eye) to both eyes in rabbits. Timolol is eliminated from the aqueous humor much faster than from the pigmented tissues iris and ciliary body.
Metabolism: Tafluprost: The principal metabolic pathway of tafluprost in human, which was tested in vitro, is the hydrolysis to the pharmacologically active metabolite, tafluprost acid, which is further metabolized by glucuronidation or beta-oxidation. Products of beta-oxidation, 1,2-dinor and 1,2,3,4-tetranor tafluprost acids, which are pharmacologically inactive, may be glucuronidated or hydroxylated. Cytochrome P450 (CYP) enzyme system is not involved in the metabolism of tafluprost acid. Based on the study in rabbit corneal tissue and with purified enzymes, the main esterase responsible for the ester hydrolysis to tafluprost acid is carboxyl esterase. Butylcholine esterase but not acetylcholine esterase may also contribute to the hydrolysis.
Timolol: Timolol is metabolized in the liver primarily by CYP2D6 enzyme into inactive metabolites, which are excreted primarily through the kidneys.
Elimination: Tafluprost: Following once daily administration of ³H-tafluprost (0.005% ophthalmic solution; 5 μl/eye) for 21 days to both eyes in rats, approximately 87% of the total radioactive dose was recovered in the excreta. Percent of the total dose excreted in urine was approximately 27-38% and approximately 44-58% of the dose was excreted in the feces.
Timolol: Apparent elimination half-life from the human plasma is about 4 hours. Timolol is extensively metabolised in the liver and the metabolites are excreted in the urine in addition to 20 % unchanged timolol following oral administration.

Tapcom: Open angle glaucoma and ocular hypertension.
Tapcom-S: 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, and who would benefit from preservative free eye drops.

Tapcom: Instill 1 drop in the affected eye(s) once daily.
Precautions: Do not use more than once daily because more frequent administration may lessen the IOP lowering effect.
Tapcom-S: Recommended therapy is one eye drop in the conjunctival sac of the affected eye(s) once daily.
If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.
TAPCOM-S is a preservative free sterile solution packaged in a single-dose container. For single use only, one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use.
Ocular use: To reduce the risk of darkening of the eyelid skin the patients should wipe off any excess solution from the skin.
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase of local activity.
If more than one topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart.
Contact lenses should be removed before instillation of the eye drops and may be reinserted after 15 minutes.
Patients should be instructed to avoid allowing the container to come into contact with the eye or surrounding structures as this could cause injury to the eye.
Patients should also be instructed that ocular solutions, if handled improperly, can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions.

Tapcom: No particulars.
Tapcom-S: A topical overdose with tafluprost is not likely to occur or to be associated with toxicity.
There have been reports of inadvertent overdosage with timolol resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking agents such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest.
If overdose with TAPCOM-S occurs, treatment should be symptomatic and supportive. Timolol does not dialyse readily.

Tapcom: 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.
Tapcom-S: Hypersensitivity to the active substances or to any of the excipients.
Reactive airway disease including bronchial asthma, or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.

Tapcom: 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 chronotropidinotropic 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 above 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 arc 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.
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.
Tapcom-S: Systemic effects: Like other topically applied ophthalmic agents, tafluprost and timolol are absorbed systemically. Due to the beta-adrenergic component timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see Dosage & Administration.
Cardiac disorders: In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular disorders: Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution. Respiratory disorders: Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. TAPCOM-S should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.
Hypoglycemia/diabetes: Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Beta-blockers may also mask the signs of hyperthyroidism. Abrupt withdrawal of beta -blocker therapy may precipitate a worsening of symptoms.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents: The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol (a component of TAPCOM-S) is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended.
Angle-closure glaucoma: In patients with angle-closure glaucoma, the immediate objective of treatment is to reopen the angle. This requires constricting the pupil with a miotic. Timolol has little or no effect on the pupil. When timolol is used to reduce elevated intraocular pressure in angle-closure glaucoma it should be used with a miotic and not alone.
Anaphylactic reactions: While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.
Choroidal detachment: Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
Surgical anaesthesia: Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin and increased iris pigmentation which are related to tafluprost therapy. 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.
Use in Children: Tapcom: The safety of this product in low-birth-weight infants, neonates, infants or children has not been established. (No clinical experience.)
Use in Elderly: Tapcom: Because physiological function is generally reduced in the elderly, caution should be exercised.

Use in Pregnancy: Tapcom: 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 μg/mL), or about 420 times the plasma concentration of unbound tafluprost (less than 0.24 μg/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.
Tapcom-S: There are no or limited amount of data from the use of TAPCOM-S in pregnant women.
Women of childbearing potential have to use effective contraception during TAPCOM-S treatment.
TAPCOM-S should not be used during pregnancy unless clearly necessary (in case no other treatment options are available).
Tafluprost: There are no adequate data for 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. The potential risk for humans is unknown.
Timolol: There are no adequate data for the use of timolol in pregnant women. Timolol should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see Dosage & Administration.
Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If TAPCOM-S is administered until delivery, the neonate should be carefully monitored during the first days of life.
Use in Lactation: Tapcom: 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).
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.
Tapcom-S: Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see Dosage & Administration.
It is unknown whether tafluprost and/or its metabolites are excreted in human milk. Available toxicological data in animals have shown excretion of tafluprost and/or its metabolites in milk. However, at therapeutic doses of tafluprost in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms in the infant.
As a precautionary measure lactation is not recommended if treatment with TAPCOM-S is required.
Fertility: There are no data on the effects of TAPCOM-S on human fertility.

Tapcom: 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: lris 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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Tapcom-S: In clinical studies, over 484 patients have been treated with TAPCOM-S. The most frequently reported treatment-related adverse event was conjunctival/ocular hyperaemia. It occurred in approximately 7% of the patients participating in the clinical studies in Europe, was mild in most cases, and was associated with discontinuation of treatment in 1.2% of patients. The adverse reactions reported in the clinical studies using TAPCOM-S were limited to those earlier reported for either of the single active substances tafluprost or timolol. No new adverse reactions specific for TAPCOM-S were observed in the clinical studies. The majority of adverse reactions reported were ocular, mild or moderate in severity and none were serious.
Like other topically applied ophthalmic agents, tafluprost and timolol are absorbed systemically. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
The following adverse reactions have been reported with TAPCOM-S during clinical trials (within each frequency grouping, adverse reactions are presented in order of decreasing frequency).
The frequency of possible adverse reactions listed below is defined using the following convention: (see Tables 5 & 6).

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Additional adverse reactions that have been seen with either of the active substances (tafluprost or timolol), and may potentially occur also with TAPCOM-S are listed below: (see Tables 7 and 8).

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Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.

Tapcom: Since this product contains timolol malate, caution should be exercised in the concomitant use of the following drugs. (See Table 9.)

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Tapcom-S: No interaction studies have been performed.
There is a potential for additive effects resulting in hypotension and/or marked bradycardia when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine.
Oral beta-adrenergic blocking agents may exacerbate the rebound hypertension which can follow the withdrawal of clonidine.
Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

Tapcom: 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 cause discoloration of the lenses. Wait at least 15 minutes before wearing the contact lenses again.

Tapcom: Keep below 25°C under protection from light.
Tapcom-S: Store in a refrigerator (2°C-8°C). After opening the foil pouch: The single-dose containers can be used for 28 days.
Keep the single-dose containers in the original foil pouch in order to protect from light.
Do not store above 25°C.
Discard an opened single-dose container with any remaining solution immediately after use.

Antiglaucoma Preparations

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

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