Timatear 5 mg, 0,3 mg Eye Drop

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are not sufficiently responsive to a topical beta-blocker or prostaglandin analogue given alone.

Posology

Adults (including the elderly) The recommended dose is one (1) drop of TIMATEAR in the affected eye(s) once daily, administered in the morning or in the evening. It should be administered at the same time each day. If a dose is missed, treatment should continue with the next dose as planned. The daily dose should not exceed one drop in the affected eye(s) daily.

Special populations

Renal and hepatic impairment No data of use in patients with hepatic or renal impairment is available. Hence, caution should be used in treating such patients.

Paediatric population The safety and efficacy of TIMATEAR in children have not yet been established. No data are available. Its use is not recommended in children or adolescents.

Method of administration

For ophthalmic use. If more than one topical ophthalmic medicine is being used, the medicines should be administered at least five minutes apart. 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 in local activity.

• Hypersensitivity to the active substances, bimatoprost and timolol or to any of the excipients listed in section 6.1.
• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sino-atrial block, second- or third-degree atrioventricular block (not controlled with pace-maker), overt cardiac failure, cardiogenic shock.

Systemic effects

The active substances (bimatoprost / timolol) in TIMATEAR may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seen with systemic beta-blockers may occur. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Cardiac disorders

Patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina, cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and therapy with other medicines should be considered. Patients with cardiovascular diseases should be monitored for signs of deterioration of these diseases and of adverse reactions. Patients with a history of severe cardiac disease should be monitored for signs of cardiac failure and their pulse rates should be monitored. Cardiac reactions, including, death in association with cardiac failures have been reported following administration of timolol maleate. Beta-blockers should only be given with caution to patients with first degree heart block due to its negative effect on conduction time.

Vascular disorders

Patients with severe peripheral circulatory disturbance/disorder (i.e. severe forms of Raynaudu2019s disease or -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. TIMATEAR 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.

Endocrine disorders

Beta-adrenergic blocking medicines may increase the hypoglycaemic effect of medicines used to treat diabetes, and can mask the signs and symptoms of hypoglycaemia. They should be used with caution in patients with spontaneous hypoglycaemia or diabetes (especially those with labile diabetes), who are receiving insulin or oral hypoglycaemic medicines. Therapy with beta-adrenergic blocking medicines may mask certain signs and symptoms of hyperthyroidism. Abrupt withdrawal of therapy may precipitate a worsening of this condition.

Corneal diseases

Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.

Other beta - blocking medicines

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to the patients already receiving a systemic beta-blocking medicine. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking medicines is not recommended (see section 4.5).

Anaphylactic reactions

When treated with beta-adrenergic blocking medicines, patients with a history of atopy or severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens. They may be 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.

Hepatic

Bimatoprost has no adverse reactions on liver function over 24 months in patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline. There are no known adverse reactions on liver function due to ophthalmic timolol administration.

Ocular

Before treatment is initiated, patients should be informed of the possibility of eyelash growth, darkening of the eyelid skin or periocular skin and increased iris pigmentation since these have been associated with bimatoprost and TIMATEAR treatment. Some of these changes may be permanent and may result in differences in appearance between the eyes if only one eye is treated. After treatment discontinuation, pigmentation of iris may be permanent. After 12 months treatment, the incidence of iris pigmentation is 0,2 %. After 12 months treatment with bimatoprost eye drops alone, the incidence is 1,5 % and does not increase following 3 years treatment.

The pigmentation change is because of increased melanin content in the melanocytes rather than due to an increase in the number of melanocytes. The long-term effects of increased iridial pigmentation are not known. Iris colour changes seen with ophthalmic bimatoprost administration may not be noticeable for several months to years. Neither nevi nor freckles of the iris appear to be affected by treatment. Periorbital tissue pigmentation has been reported to be reversible in some patients.

Macular oedema, including cystoid macular oedema, has been reported. Therefore, TIMATEAR should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, and in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).

The use of bimatoprost in combination with timolol has not been studied in patients with inflammatory ocular conditions; neovascular, inflammatory, angle-closure glaucoma; congenital glaucoma or narrow angle glaucoma. TIMATEAR should be used with caution in patients with active intraocular inflammation (e.g. uveitis) because the inflammation may be exacerbated.

In studies of bimatoprost 0,3 mg/ml in patients with glaucoma or ocular hypertension, it has been reported that more frequent exposure of the eye to more than one dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using TIMATEAR with other prostaglandin analogues should be monitored for intraocular pressure changes.

Skin

It is probable for hair growth to occur in areas where TIMATEAR solution repeatedly comes into contact with the skin surface. Thus, it is important to apply TIMATEAR as instructed and to avoid contact with the cheek or other skin areas.

Preservative - Benzalkonium chloride

As the possibility of adverse effects on the corneal permeability, and the danger of disruption of the corneal epithelium with prolonged or repeated usage of benzalkonium chloride preserved ophthalmological preparations, cannot be excluded, regular ophthalmological examination is required. Caution should be exercised in the use of benzalkonium chloride preserved topical medication over an extended period in patients with extensive ocular surface disease. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Therefore, monitoring is required with frequent or prolonged use of TIMATEAR in dry eye patients or where the cornea is compromised.

Contact lenses

TIMATEAR contains benzalkonium chloride as a preservative, which may cause eye irritation and be absorbed by soft contact lenses. Contact lenses must be removed prior to instillation of TIMATEAR and may be reinserted 15 minutes following administration. Furthermore, benzalkonium chloride is known to discolour soft contact lenses and contact with soft contact lenses must be avoided.

Paediatric population Safety and effectiveness in children have not been established.

No specific interaction studies have been performed with the bimatoprost / timolol fixed combination. Patients who are receiving a systemic (e.g. oral or intravenous) beta-adrenergic blocking medicine and TIMATEAR should be observed for potential additive effects of beta-blockage, both systemic and on intraocular pressure. There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when timolol containing eye drops are administered concomitantly with oral calcium channel blockers or beta-blockers, guanethidine, anti-dysrhythmics (including amiodarone), digoxin or parasympathomimetics and other anti-hypertensives. Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during concurrent treatment of CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) with timolol. Beta-blockers may increase the hypoglycaemic effect of antidiabetic medicines. Beta-blockers can mask the signs and symptoms of hypoglycaemia. The hypertensive reaction to sudden withdrawal of clonidine treatment can be potentiated when taking beta-blockers. Mydriasis resulting from concurrent use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

Pregnancy

There is no adequate data from the use of the bimatoprost / timolol fixed combination in pregnant women. Bimatoprost No adequate clinical data in exposed pregnancies are available. Animal studies have shown reproductive toxicity at high maternotoxic doses. Timolol Epidemiological studies have not revealed malformative effects but shown a risk for intra-uterine growth retardation when beta-blockers are administered by the oral route. Signs and symptoms of beta-blockade including bradycardia, hypotension, respiratory distress and hypoglycaemia, have been observed in the neonate when beta-blockers have been administered until delivery. If TIMATEAR is administered until delivery, the neonate should be closely monitored during the first days of life. Animal studies with timolol have shown reproductive toxicity at doses significantly higher than would be used in clinical practice.

Breastfeeding

Timolol Timolol is excreted in breast milk. Bimatoprost It is unknown if bimatoprost is excreted in human breast milk. TIMATEAR should not be used by breastfeeding women.

Fertility

There are no data on the effects of TIMATEAR on human fertility.

TIMATEAR has negligible influence on the ability to drive and use machines. If transient blurred vision occurs following administration, the patient should be advised to wait until the vision clears before driving or operating machinery.

a. Summary of the safety profile

Most adverse reactions are ocular in nature, mild in severity and not serious. The most commonly reported side effect is conjunctival hyperaemia.

b. Tabulated summary of adverse reactions

Table 1: Bimatoprost / Timolol as in TIMATEAR

System Organ Class Frequency Adverse Event Immune system disorders Frequency unknown Hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, eye allergy. Psychiatric disorders Frequency unknown Insomnia, nightmare. Nervous system disorders Frequent Headache. Frequency unknown Dysgeusia, dizziness. Eye disorders Frequent Conjunctival hyperaemia, growth of eyelashes, superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus, conjunctival irritation, visual acuity worsened, blepharitis, eyelid oedema, eye irritation, lacrimation increased. Less frequent Iritis, conjunctival oedema, eyelid pain, epiphora, asthenopia, trichiasis, abnormal sensation of the eye, iris hyperpigmentation, periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus, eyelid ptosis, enophthalmos, lagophthalmos, eyelid retraction, eyelash discolouration (darkening). Frequency unknown Cystoid macular oedema, eye swelling, blurred vision, ocular discomfort. Cardiac disorders Frequency unknown Bradycardia. Vascular disorders Frequency unknown Hypertension. Respiratory, thoracic and mediastinal disorders Frequent Rhinitis. Less frequent Dyspnoea. Frequency unknown Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), asthma. Skin and subcutaneous tissue disorders Frequent Blepharal pigmentation, hirsutism, skin hyperpigmentation (periocular). Frequency unknown Alopecia, skin discolouration (periocular). General disorders and administration site conditions Frequency unknown Fatigue. Additional side effects that have been seen with either of the active substances (bimatoprost or timolol) and may potentially occur also with TIMATEAR are listed below in Table 2:

Table 2 System Organ Class Frequency Adverse Event Immune system disorders Frequency unknown Systemic allergic reactions including anaphylaxis. Metabolism and nutrition disorders Frequency unknown Hypoglycaemia. Psychiatric disorders Frequency unknown Depression, memory loss, hallucination. Nervous system disorders Frequency unknown Syncope, cerebrovascular accident, increase in signs and symptoms of myasthenia gravis, paraesthesia, cerebral ischaemia. Eye disorders Frequency unknown Decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis, allergic conjunctivitis, cataract, blepharospasm, retinal haemorrhage, uveitis. Ear and labyrinth disorders Frequency unknown Tinnitus. Cardiac disorders Frequency unknown Atrioventricular block, cardiac arrest, dysrhythmia, cardiac failure, congestive heart failure, chest pain, palpitations, oedema, pulmonary oedema, worsening of angina pectoris. Vascular disorders Frequency unknown Hypotension, claudication, Raynaudu2019s phenomenon, cold hands and feet. Respiratory, thoracic and mediastinal disorders Frequency unknown Asthma exacerbation, COPD exacerbation, cough, nasal congestion, respiratory failure, upper respiratory infection. Gastrointestinal Disorders Frequency unknown Nausea, diarrhoea, dyspepsia, dry mouth, abdominal pain, vomiting, anorexia. Skin and subcutaneous tissue disorders Frequency unknown Psoriasiform rash or exacerbation of psoriasis, skin rash, abnormal hair growth. Musculoskeletal and connective tissue disorders Frequency unknown Myalgia, systemic lupus erythematosus. Reproductive system and breast disorders Frequency unknown Decreased libido, sexual dysfunction, Peyronieu2019s disease, retroperitoneal fibrosis. General disorders and administration of site conditions Frequency unknown Asthenia, peripheral oedema. Investigations Frequency unknown Abnormal liver function tests.

No cases of overdose have been reported, and it is unlikely to occur following ocular administration or to be associated with toxicity. Symptoms of systemic timolol overdose include bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest. Timolol does not readily dialyse.

If TIMATEAR is accidentally ingested, the following information may be of use: in two-week oral rat and mouse studies, doses up to 100 mg/kg/day of bimatoprost did not produce toxicity. This dose is at least 70-times higher than the accidental dose of one bottle of TIMATEAR in a 10 kg child. In the event of overdose, treatment should be symptomatic and supportive.