Trinopthal Co 50 μg/mL and 5 mg/mL eye drops, Solution

Reduction of intraocular pressure (IOP) in patients with open angle glaucoma and ocular hypertension who are not controlled on, or are intolerant to, monotherapy with compounds other than latanoprost and timolol.

Posology
Adults (including the elderly)
One drop in the effected eye(s) once daily. The dosage of TRINOPTHAL CO should not exceed once daily since it has been shown that more frequent administration of latanoprost decreases the intraocular pressure lowering effect. If one dose is missed, treatment should continue with the next dose as planned. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced.
Paediatric population
The safety and efficacy of TRINOPTHAL CO in children has not yet been established.
Method of administration
For ophthalmic use. The screwcap should be removed before use. If more than one topical ophthalmic medicine is being used, the medicines should be administered at least five minutes apart.

• Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.
• Bronchial asthma or a history of bronchial asthma, chronic obstructive pulmonary disease (COPD).
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second- or third-degree atrioventricular block (not controlled with pace-maker), cardiac failure, cardiogenic shock.
• Active herpes simplex keratitis or recurrent herpetic keratitis specifically associated with prostaglandin analogues (see section 4.4).

Latanoprost
Iris pigmentation changes
Latanoprost may gradually increase the brown pigment of the iris. The eye colour change is due to increased melanin content in the stromal melanocytes of the iris, rather than to an increase in the number of melanocytes. Typically, the brown pigmentation around the pupil spreads concentrically towards the periphery of the iris and the entire iris or parts of the iris become more brownish. The change in iris colour is mild in the majority of cases and may not be detected clinically. The increase in iris pigmentation in one or both eyes has been documented predominantly in patients who have mixed colour irides that contain the colour brown at baseline. Neither nevi nor freckles of the iris have been affected by treatment. No accumulation of pigment in the trabecular meshwork or elsewhere in the anterior chamber has been observed in clinical trials. In a clinical trial designed to assess iris pigmentation over five years, there was no evidence of adverse consequences due to increased pigmentation even when administration of latanoprost continued. These results are consistent with post-marketing clinical experience since 1996. In addition, IOP reduction was similar in patients regardless of the development of increased iris pigmentation. Therefore, treatment with latanoprost can be continued in patients who develop increased iris pigmentation. These patients should be examined regularly and, depending on the clinical situation, treatment may be stopped. Onset of increased iris pigmentation typically occurs within the first year of treatment, rarely during the second or third year, and has not been seen after the fourth year of treatment. The rate of progression of iris pigmentation decreases with time and is stable by five years. The effects of increased pigmentation beyond five years have not been evaluated. During clinical trials, the increase in brown iris pigment has not been shown to progress further upon discontinuation of treatment, but the resultant colour change may be permanent.
Eyelid and eyelash changes
Eyelid skin darkening, which may be reversible, has been reported in association with the use of latanoprost. Latanoprost may gradually change eyelashes and vellus hair in the treated eye; these changes include increased length, thickness, pigmentation, and number of lashes or hairs, and misdirected growth of eyelashes. Eyelash changes are reversible upon discontinuation of treatment.
The potential for heterochromia exists for patients receiving unilateral treatment.
Macular oedema
Macular oedema, including cystoid macular oedema, has been reported during treatment with latanoprost. These reports have mainly occurred in aphakic patients, in pseudophakic patients with torn posterior lens capsule, or in patients with known risk factors for macular oedema. Caution is recommended when using TRINOPTHAL CO in these patients.
Glaucoma
There is no documented experience with latanoprost-timolol in inflammatory, neovascular, chronic angle closure or congenital glaucoma, in open-angle glaucoma of pseudophakic patients and in pigmentary glaucoma. Therefore, it is recommended that TRINOPTHAL CO should be used with caution in these conditions until more experience is obtained.
Herpetic keratitis
Latanoprost should be used with caution in patients with a history of herpetic keratitis and is contraindicated in cases of active herpes simplex keratitis and in patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogues (see section 4.3).
Timolol
Systemic effects
The same adverse reactions found with systemic administration of beta-adrenergic blocking medicines may occur with their topical administration. Patients with a history of severe cardiac disease should be monitored closely for signs of cardiac failure. The following cardiac and respiratory reactions may occur after topical application of timolol maleate as in TRINOPTHAL CO:

• Aggravation of Prinzmetalu2019s angina.
• Aggravation of peripheral and central circulatory disorders.
• Hypotension.
• Cardiac failure resulting in death.
• Severe respiratory reactions, including fatal bronchospasm in patients with asthma.
• Bradycardia.

Specific interaction studies have not been performed with TRINOPTHAL CO. The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when TRINOPTHAL CO is given to patients already receiving an oral beta-adrenergic blocking medicine. The use of two or more topical beta-adrenergic blocking medicines is not recommended.
There have been reports of paradoxical elevations in IOP following the concomitant ophthalmic administration of two prostaglandin analogs. Therefore, the use of two or more prostaglandins, prostaglandin analogs, or prostaglandin derivatives is not recommended. The potential exists for additive effects resulting in hypotension and/or marked bradycardia when eye drops containing timolol are administered with calcium-channel blockers, catecholamine-depleting medicines or beta-blocking medicines, anti-arrhythmics (including amiodarone and quinidine), digitalis glycosides, parasympathomimetics, narcotics and monoamine oxidase (MAO) inhibitors. 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 has occasionally been reported when timolol is given with adrenaline, although TRINOPTHAL CO alone has little or no effect on pupil size. Beta-blockers may increase the hypoglycaemic effect of anti-diabetic medicines (see section 4.4). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers. The concomitant use of TRINOPTHAL CO with hypoglycaemic medicines, phenothiazines and various anti-arrhythmic medicines may have interactions with life-threatening consequences.

Pregnancy
The safety in pregnancy has not been established.
Breastfeeding
TRINOPTHAL CO should not be used in women who are breastfeeding their infants. Breastfeeding should be stopped as timolol is excreted into breast milk and latanoprost and its metabolites may pass into breast milk.
Fertility
Neither Latanoprost nor timolol have been found to have any effect on male or female fertility.

TRINOPTHAL CO has minor influence on the ability to drive and use machines. Instillation of eye drops may cause transient blurring of vision. Until this has resolved, patients should not drive or use machines. It is not always possible to predict to what extent TRINOPTHAL CO may interfere with the daily activities of a patient. Patients should ensure that they do not engage in the above activities until they are aware of the measure to which TRINOPTHAL CO affects them.

a. Summary of the safety profile
For latanoprost, the majority of adverse reactions relate to the ocular system. In data from the extension phase of the latanoprost and timolol, 16 u2013 20 % of patients developed increased iris pigmentation, which may be permanent. In an open 5-year latanoprost safety study, 33 % of patients developed iris pigmentation (see section 4.4). The most frequent findings of increased iris pigmentation were in patients with green-brown, yellow-brown and blue/grey/brown irides. In patients with homogenously blue, grey, green or brown eyes, the change was only rarely seen. Darkening, thickening and lengthening of the eye lashes has been reported. Other ocular adverse reactions are generally transient and occur on dose administration. Undesirable effects which may occur frequently (usually transient ocular effects) are irritation of the eye, including stinging, burning and itching, eye hyperaemia, corneal disorders, conjunctivitis, blepharitis, eye pain, headache and skin rash. For timolol, the most serious adverse reactions are systemic in nature, including bradycardia, dysrhythmia, congestive heart failure, bronchospasm and allergic reactions. Like other topically applied ophthalmic medicines, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta blocking medicines. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
b. Tabulated summary of adverse reactions
Latanoprost / Timolol
System Organ Class Frequency Adverse Event
Infections and infestations Frequent Infection; sinusitis; upper respiratory tract infection.
Metabolism and nutrition disorders Frequent Diabetes mellitus; hypercholesterolemia.
Psychiatric disorders Frequent Depression.
Nervous system disorders Frequent Headache.
Eye disorders Frequent Hypertrichosis (eyelash and vellus hair changes of the eyelids; increased length, thickness, pigmentation, and number of eyelashes); abnormal vision; blepharitis; cataract; conjunctival disorder; conjunctivitis; corneal disorder; errors of refraction; eye hyperaemia; eye irritation (including stinging, burning, itching, foreign body sensation); eye pain; increased iris pigmentation; keratitis; photophobia; visual field defect.
Vascular disorders Frequent Hypertension.
Skin and subcutaneous tissue disorders Frequent Rash; skin disorder. Less frequent Pruritis.
Musculoskeletal and connective tissue disorders Frequent Arthritis.

Apart from ocular irritation and conjunctival hyperaemia, no other ocular or systemic side effects are known if latanoprost is overdosed. Symptoms of systemic timolol overdosage are bradycardia, hypotension, bronchospasm and cardiac arrest. If such symptoms occur, the treatment should be symptomatic and supportive. If latanoprost is accidentally ingested, the following may be useful: One 2,5 mL bottle contains 125 micrograms latanoprost. More than 90 % is metabolised during the first pass through the liver. Intravenous infusion of 3 u03bcg/kg in healthy volunteers induced no symptoms, but a dose of 5,5 u2013 10 u03bcg/kg caused nausea, abdominal pain, dizziness, fatigue, hot flushes and sweating. In patients with moderate bronchial asthma, bronchoconstriction was not induced by latanoprost such as included in TRINOPTHAL CO when applied topically on the eyes in a dose of seven times the clinical dose of latanoprost. Studies have shown that timolol does not dialyse readily. There have been reports of inadvertent overdosage with TRINOPTHAL CO resulting in systemic effects similar to those seen with systemic beta-adrenergic blocking medicines such as dizziness, headache, shortness of breath, bradycardia, bronchospasm, and cardiac arrest.