Ganfort 0,3 mg/ml Eye drops, solution

Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to a topical beta-blocker or prostaglandin analogue(s) given alone.

Posology

Recommended dosage in adults (including the elderly) The recommended dose is one drop of GANFORT in the affected eye(s) once daily, administered either in the morning or in the evening. 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.

Special populations

Use in renal and hepatic impairment GANFORT has not been studied in patients with hepatic or renal impairment. Therefore caution should be used in treating such patients.

Paediatric population GANFORT has only been studied in adults and therefore its use is not recommended in children or adolescents.

Method of administration

If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart. When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced.

• Hypersensitivity to the bimatoprost, timolol or to any of the excipients in GANFORT 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 a pace-maker, overt cardiac failure, cardiogenic shock.

The components of GANFORT may be absorbed systemically. 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. To reduce systemic absorption, see section 4.2.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary artery disease, Prinzmetalu2019s angina and cardiac failure) and hypotension, therapy with beta-blockers, as in GANFORT should be critically assessed and therapy with other active substances should be considered. GANFORT should be used with caution in patients with cardiovascular disease (e.g. coronary heart disease, Prinzmetalu2019s angina, first degree heart block and cardiac failure) and hypotension. Patients with cardiovascular diseases should be monitored for signs of deterioration of these diseases, and of adverse reactions. Due to its negative effect on conduction time, GANFORT should only be given with caution to patients with first degree heart block.

Vascular disorders

Patients with severe peripheral circulatory disturbances/disorders (i.e. severe forms of Raynaudu2019s disease or Raynaudu2019s syndrome) should be treated with caution.

Respiratory disorders

Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of timolol maleate, as in GANFORT. GANFORT 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

Timolol, as in GANFORT should be administered with caution in patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) as beta-blockers may mask the signs or symptoms of acute hypoglycaemia. Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Timolol, as in GANFORT 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, as in GANFORT, is given to patients already receiving a systemic beta-blocking medicine. Caution should be exercised when used concomitantly with systemic beta-adrenergic blocking medicines. The response of these patients should be closely observed. The use of two beta-adrenergic blocking medicines is not recommended (see section 4.5).

Anaphylactic reactions

While taking timolol, as in GANFORT, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to a repeated challenge with such allergens and unresponsive to the usual dose of (epinephrine) adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy such as timolol, after filtration procedures.

Surgical anaesthesia

Ophthalmic beta-blockers may impair compensatory tachycardia and increase risk of hypotension when used in conjunction with anaesthetics. Timolol, such as in GANFORT, may block systemic beta-agonist effects e.g. of epinephrine (adrenaline). The anaesthesiologist should be informed when the patient is receiving GANFORT.

Hepatic

In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost had no adverse reactions on liver function over 24 months. There are no known adverse reactions of ocular timolol, as in GANFORT, on liver function.

Ocular

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

Macular oedema, including cystoid macular oedema has been reported during treatment with GANFORT. GANFORT should be used with caution in aphakic patients, pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy). GANFORT should be used with caution in patients with active intraocular inflammation (e.g. uveitis) because the inflammation may be exacerbated.

Skin

There is a potential for hair growth to occur in areas where GANFORT solution comes repeatedly in contact with the skin surface. Thus, it is important to apply GANFORT as instructed and avoid it running onto the cheek or other skin areas.

Excipients

The preservative in GANFORT, benzalkonium chloride, may cause eye irritation and may also be absorbed by soft contact lenses. Contact lenses must be removed prior to application, with at least a 15-minutes wait before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Contact with soft contact lenses must be avoided. Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Therefore monitoring is required with frequent or prolonged use of GANFORT in dry eye patients or where the cornea is compromised. 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 medicines over an extended period, in patients with extensive ocular surface disease.

Other conditions

GANFORT has not been studied in patients with inflammatory ocular conditions, neovascular glaucoma, inflammatory glaucoma, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma. In studies in patients with glaucoma or ocular hypertension with bimatoprost ophthalmic solution 0,03 %, it has been shown that more frequent exposure of the eye to more than one dose of bimatoprost (as in GANFORT) daily may decrease the IOP-lowering effect. Patients using GANFORT with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

No specific interaction studies have been performed with GANFORT. Patients who are receiving a systemic (e.g. oral or intravenous) beta-adrenergic blocking medicine and GANFORT 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 an ophthalmic beta-blocker solution, such as GANFORT, is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking medicines, anti-dysrhythmics (including amiodarone), digoxin or parasympathomimetics and other anti-hypertensives. Timolol as in GANFORT can mask the signs and symptoms of and the bodyu2019s reaction to hypoglycaemia (see section 4.8). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers such as in GANFORT. Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine, selective serotonin reuptake inhibitors (SSRIs)) and timolol. Mydriasis resulting from concomitant use of ophthalmic beta-blockers such as in timolol and adrenaline (epinephrine) has been reported.

Pregnancy

There are no adequate data from the use of GANFORT in pregnant women. 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 GANFORT is administered until delivery, the neonate should be carefully monitored during the first days of life.

Breastfeeding

Timolol is excreted in breastmilk. It is not known if bimatoprost is excreted in human breastmilk. Women on GANFORT should not breastfeed their infants.

Transient blurred vision may occur at installation, therefore the patient should wait until the vision clears before driving or using machinery.

Summary of the safety profile

The most commonly reported side effect was conjunctival hyperaemia in approximately 26 % of patients and led to discontinuation in 1,5 % of patients.

Tabulated summery of adverse reactions

Table 1 presents the adverse reactions that have been reported during clinical studies with all GANFORT formulations (GANFORT multi-dose and bimatoprost/timolol single-dose formulation) (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness) or in the post-marketing period. The frequency is defined as follows: Very Common (u2265 1/10); Common (u22651/100 to <1/10); Uncommon (u2265 1/1 000 to < 1/100); Rare (u2265 1/10 000 to < 1/1 000); Very Rare (< 1/10 000); Not known (cannot be estimated from available data).

Table 1 System organ class Frequency Adverse reaction Immune system disorders Not known Hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, eye allergy Psychiatric disorders Not known Insomnia 2 , nightmare 2 Nervous system disorders Common Headache Not known Dysgeusia 2 , dizziness Eye disorders Very common Conjunctival hyperaemia, growth of eyelashes Common Superficial punctate keratitis, corneal erosion 2 , burning sensation 2 , conjunctival irritation 1 , eye pruritus, stinging sensation in the eye 2 , foreign body sensation, dry eye, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance 2 , eyelid pruritus, visual acuity worsened 2 , blepharitis 2 , eyelid oedema, eye irritation, lacrimation increased Uncommon Iritis 2 , conjunctival oedema 2 , eyelid pain 2 , abnormal sensation in the eye 1 , asthenopia, trichiasis 2 , iris hyperpigmentation 2 , periorbital and lid changes associated with periorbital fat atrophy and skin tightness resulting in deepening of eyelid sulcus, eyelid ptosis, enophthalmos, lagophthalmos and eyelid retraction 1&2 , eyelash discolouration (darkening) 1 , epiphora Not known Cystoid macular oedema 2 , eye swelling, blurred vision 2 , ocular discomfort Cardiac disorders Not known Bradycardia Vascular disorders Not known Hypertension Respiratory, thoracic and mediastinal disorders Common Rhinitis 2 Uncommon Dyspnoea Not known Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) 2 , asthma Skin and subcutaneous tissue Common Blepharal pigmentation 2 , hirsutism 2 , periocular skin hyperpigmentation disorders Not known Alopecia, periocular skin discolouration General disorders and administration site conditions Not known Fatigue 1 Adverse reactions only observed with bimatoprost/timolol single-dose formulation 2 Adverse reactions only observed with Ganfort multi-dose formulation GANFORT (bimatoprost/timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking medicines. To reduce the systemic absorption, see section 4.2. Additional side effects that have been seen with one of the components and may potentially occur also with GANFORT are listed below in Table 2.

Table 2 System Organ Class Adverse reaction Immune system disorders Systemic allergic reactions including anaphylaxis 1 , urticarial, localised and generalised rash 1 , pruritus 1 Metabolism and nutrition disorders Hypoglycaemia 1 Psychiatric disorders Behavioural changes and psychic disturbances including depression 1 , memory loss 1 , hallucination 1 , anxiety 1 , disorientation 1 , confusion 1 , nervousness 1 , somnolence 1 Nervous system disorders Syncope 1 , cerebrovascular accident 1 , increase in signs and symptoms of myasthenia gravis 1 , paraesthesia 1 , cerebral ischaemia 1 Eye disorders Decreased corneal sensitivity 1 , diplopia 1 , ptosis 1 , choroidal detachment following filtration surgery 1 (see section 4.4), keratitis 1 , blepharospasm 2 , retinal haemorrhage 2 , uveitis 2 , refractive changes (due to withdrawal of miotic therapy in some cases) 1 , pseudopemphigoid 1 , signs and symptoms of ocular irritation including conjunctivitis 1 , allergic conjunctivitis 2 Ear and labyrinth disorders Tinnitus 1 Cardiac disorders Atrioventricular block 1 , cardiac arrest 1 , dysrhythmia 1 , cardiac failure 1 , congestive heart failure 1 , chest pain 1 , palpitations 1 , oedema 1 , pulmonary oedema 1 , worsening of angina pectoris 1 Vascular disorders Hypotension 1 , Raynaudu2019s phenomenon 1 , cold hands and feet 1 , claudication 1 Respiratory, thoracic and mediastinal disorders Asthma exacerbation 2 , COPD exacerbation 2 , cough 1 , nasal congestion 1 , respiratory failure 1 , upper respiratory infection 1 Gastrointestinal disorders Nausea 1,2 , diarrhoea 1 , dyspepsia 1 , dry mouth 1 , abdominal pain 1 , vomiting 1 , anorexia 1 Skin and subcutaneous tissue disorders Psoriasiform rash 1 , exacerbation of psoriasis 1 , skin rash 1 , abnormal hair growth 2 Musculoskeletal and connective tissue disorders Myalgia 1 , systemic lupus erythematosus 1 Reproductive system and breast disorders Sexual dysfunction 1 , decreased libido 1 , Peyronieu2019s disease 1 , retroperitoneal fibrosis 1 General disorders and administration site conditions Asthenia 1,2 , peripheral oedema 2 Investigations Liver function tests (LFT) abnormal 2 Infection and infestations Infection (primary colds and upper respiratory symptoms) 1,2

In overdose, side effects may be exacerbated and exaggerated (see section 4.8). Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest. Timolol does not dialyse readily. If overdose occurs treatment should be symptomatic and supportive.