GANFORT 0.3mg / 5mg / ml ophthalmic drops solution medication leaflet

GANFORT 0.3 mg/ml + 5 mg/ml eye drops, solution

One ml of solution contains 0.3 mg of bimatoprost and 5 mg of timolol (as 6.8 mg of timolol maleate).

Each ml of solution contains 0.05 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, solution (eye drops)

Colourless to slightly yellow solution.

Reduction of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocularhypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.

Recommended dosage in adults (including elderly)

The recommended dose is one drop of GANFORT in the affected eye(s) once daily, administeredeither in the morning or in the evening. It should be administered at the same time each day.

Existing literature data for GANFORT suggest that evening dosing may be more effective in

IOP-lowering than morning dosing. However, consideration should be given to the likelihood ofcompliance when considering either morning or evening dosing (see section 5.1).

If one dose is missed, treatment should continue with the next dose as planned. The dose should notexceed one drop in the affected eye(s) daily.

GANFORT has not been studied in patients with hepatic or renal impairment. Therefore cautionshould be used in treating such patients.

The safety and efficacy of GANFORT in children aged 0 to 18 years has not been established. No dataare available.

If more than one topical ophthalmic medicinal product is to be used, each one should be instilled atleast 5 minutes apart.

When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption isreduced. This may result in a decrease in systemic side effects and an increase in local activity.

* Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

* Reactive airway disease including bronchial asthma or a history of bronchial asthma, severechronic obstructive pulmonary disease.

* Sinus bradycardia, sick sinus syndrome, sino-atrial block, second- or third degreeatrioventricular block, not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.

Like other topically applied ophthalmic medicinal products, the active substances (timolol/bimatoprost) in GANFORT may be absorbed systemically. No enhancement of the systemicabsorption of the individual active substances has been observed. Due to the beta-adrenergiccomponent, timolol, the same types of cardiovascular, pulmonary and other adverse reactions as seenwith systemic beta-blockers may occur. Incidence of systemic ADRs after topical ophthalmicadministration is lower than for systemic administration. To reduce the systemic absorption, seesection 4.2.

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiacfailure) and hypotension, therapy with beta-blockers should be critically assessed and therapy withother active substances should be considered. Patients with cardiovascular diseases should be watchedfor 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 topatients with first degree heart block.

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’sdisease or Raynaud’s syndrome) should be treated with caution.

Respiratory reactions, including death due to bronchospasm in patients with asthma have beenreported following administration of some ophthalmic beta-blockers.

GANFORT should be used with caution, in patients with mild/moderate chronic obstructivepulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

Beta-adrenergic blocking medicinal products should be administered with caution in patients subjectto spontaneous hypoglycemia or to patients with labile diabetes as beta-blockers may mask the signsand symptoms of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

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

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiatedwhen timolol is given to the patients already receiving a systemic beta-blocking agent. The response ofthese patients should be closely observed. The use of two topical beta-adrenergic blocking agents isnot recommended (see section 4.5).

Anaphylactic reactions

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reactionto a variety of allergens may be more reactive to repeated challenge with such allergens andunresponsive to the usual dose 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 anaesthesiaβ-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of adrenaline. Theanaesthesiologist should be informed when the patient is receiving timolol.

Hepatic

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

Ocular

Before treatment is initiated, patients should be informed of the possibility of eyelash growth,darkening of the eyelid or periocular skin and increased brown iris pigmentation since these have beenobserved during treatment with bimatoprost and GANFORT. Increased iris pigmentation is likely tobe 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 monthstreatment with GANFORT, the incidence of iris pigmentation was 0.2%. After 12 months treatmentwith bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 yearstreatment. The pigmentation change is due to increased melanin content in the melanocytes rather thanto an increase in the number of melanocytes. The long-term effects of increased iridial pigmentationare not known. Iris colour changes seen with ophthalmic administration of bimatoprost may not benoticeable for several months to years. Neither nevi nor freckles of the iris appear to be affected bytreatment. Periorbital tissue pigmentation has been reported to be reversible in some patients.

Macular oedema, including cystoid macular oedema, has been reported with GANFORT. Therefore,

GANFORT should be used with caution in aphakic patients, in pseudophakic patients with a tornposterior lens capsule, or in patients with known risk factors for macular oedema (e.g. intraocularsurgery, 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 incontact with the skin surface. Thus, it is important to apply GANFORT as instructed and avoid itrunning onto the cheek or other skin areas.

The preservative in GANFORT, benzalkonium chloride, may cause eye irritation. Contact lenses mustbe removed prior to application, with at least a 15-minute wait before reinsertion. Benzalkoniumchloride 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 ulcerativekeratopathy. Therefore monitoring is required with frequent or prolonged use of GANFORT in dryeye patients or where the cornea is compromised.

Other conditions

GANFORT has not been studied in patients with inflammatory ocular conditions, neovascular,inflammatory, angle-closure glaucoma, congenital glaucoma or narrow-angle glaucoma.

In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it has beenshown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily may decreasethe IOP-lowering effect. Patients using GANFORT with other prostaglandin analogues should bemonitored for changes to their intraocular pressure.

No specific interaction studies have been performed with the bimatoprost/timolol fixed combination.

There is a potential for additive effects resulting in hypotension, and/or marked bradycardia whenophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers,guanethidine, beta-adrenergic blocking agents, parasympathomimetics, anti-arrhythmics (includingamiodarone) and digitalis glycosides.

Potentiated systemic beta-blockade (e.g., decreased heart rate, depression) has been reported duringcombined 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.

There are no adequate data from the use of the bimatoprost/timolol fixed combination in pregnantwomen. GANFORT should not be used during pregnancy unless clearly necessary. To reduce thesystemic absorption, see section 4.2.

Bimatoprost

No adequate clinical data in exposed pregnancies are available. Animal studies have shownreproductive toxicity at high maternotoxic doses (see section 5.3).

Timolol

Epidemiological studies have not revealed malformative effects but shown a risk for intra uterinegrowth retardation when beta-blockers are administered by the oral route. In addition, signs andsymptoms 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 firstdays of life. Animal studies with timolol have shown reproductive toxicity at doses significantlyhigher than would be used in clinical practice (see section 5.3).

Timolol

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it isnot likely that sufficient amounts would be present in breast milk to produce clinical symptoms ofbeta-blockade in the infant. To reduce the systemic absorption, see section 4.2.

Bimatoprost

It is not known if bimatoprost is excreted in human breast milk but it is excreted in the milk of thelactating rat. GANFORT should not be used by breast-feeding women.

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

GANFORT has negligible influence on the ability to drive and use machines. As with any oculartreatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clearsbefore driving or using machines.

The adverse reactions reported in clinical studies using GANFORT were limited to those earlierreported for either of the single active substances bimatoprost and timolol. No new adverse reactionsspecific for GANFORT have been observed in clinical studies.

The majority of adverse reactions reported in clinical studies using GANFORT were ocular, mild inseverity and none were serious. Based on 12-month clinical data, the most commonly reported adversereaction was conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatorynature) in approximately 26% of patients and led to discontinuation in 1.5% of patients.

Table 1 presents the adverse reactions that have been reported during clinical studies with all

GANFORT formulations (multi-dose and single-dose) or in the post-marketing period.

Possible adverse reactions are listed by MedDRA system organ class and are based on the followingconvention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100);rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000) and not known (cannot be estimated from theavailable data). Within each frequency grouping, adverse reactions are presented in order of decreasingseriousness.

Table 1: List of adverse reactions with all GANFORT formulations (multi-dose and single-dose)

System Organ Class Frequency Adverse reaction

Immune system disorders Not known Hypersensitivity reactionsincluding signs or symptoms ofallergic dermatitis, angioedema,eye allergy

Psychiatric disorders Not known Insomnia2, nightmare2

Nervous system disorders Common Headache

Not known Dysgeusia2, dizziness

Eye disorders Very common Conjunctival hyperaemia.

Common Punctuate keratitis, cornealerosion2, burning sensation2,conjunctival irritation1, eyepruritus, stinging sensation inthe eye2, foreign body sensation,dry eye, erythema of eyelid, eyepain, photophobia, eyedischarge, visual disturbance2,eyelid pruritus, visual acuityworsened2, blepharitis2, eyelidoedema, eye irritation,lacrimation increased, growth ofeyelashes.

Uncommon Iritis2, conjunctival oedema2,eyelid pain2, abnormal sensationin the eye1, asthenopia,trichiasis2, irishyperpigmentation2, periorbitaland lid changes associated withperiorbital fat atrophy and skintightness resulting in deepeningof eyelid sulcus, eyelid ptosis,enophthalmos, lagophthalmosand eyelid retraction1&2, eyelashdiscolouration (darkening)1.

Not known Cystoid macular oedema2, eyeswelling, vision blurred2, oculardiscomfort

Cardiac disorders Not known Bradycardia

Vascular disorders Not known Hypertension

Respiratory, thoracic and Common Rhinitis2mediastinal disorders

Uncommon Dyspnoea

Not known Bronchospasm (predominantlyin patients with pre-existingbronchospastic disease) 2,asthma

Skin and subcutaneous tissue Common Blepharal pigmentation2,disorders hirsutism2, skinhyperpigmentation (periocular).

Not known Alopecia, skin discolouration(periocular)

General disorders and Not known Fatigueadministration site conditions1adverse reactions only observed with Ganfort single-dose formulation2adverse reactions only observed with Ganfort multi-dose formulation

Like other topically applied ophthalmic drugs, GANFORT (bimatoprost/timolol) is absorbed into thesystemic circulation. Absorption of timolol may cause similar undesirable effects as seen withsystemic beta-blocking agents. The incidence of systemic ADRs after topical ophthalmicadministration is lower than for systemic administration. To reduce the systemic absorption, seesection 4.2.

Additional adverse reactions that have been seen with either of the active substances (bimatoprost ortimolol), and may potentially occur also with GANFORT are listed below in Table 2:

Table 2: List of additional adverse reactions seen with either of the active substances(bimatoprost or timolol)

System Organ Class Adverse reaction

Immune system disorders Systemic allergic reactions includinganaphylaxis1

Metabolism and nutrition disorders Hypoglycaemia1

Psychiatric disorders Depression1, memory loss1, hallucination1

Nervous system disorders Syncope1, cerebrovascular accident1, increase insigns and symptoms of myasthenia gravis1,paraesthesia1, cerebral ischaemia1

Eye disorders Decreased corneal sensitivity1, diplopia1, ptosis1,choroidal detachment following filtration surgery(see section 4.4)1, keratitis1, blepharospasm2,retinal haemorrhage2, uveitis2,

Cardiac disorder Atrioventricular block1, cardiac arrest1,arrhythmia1, cardiac failure1, congestive heartfailure1, chest pain1, palpitations1, oedema1

Vascular disorders Hypotension1, Raynaud’s phenomenon1, coldhands and feet1

Respiratory, thoracic and mediastinal disorders Asthma exacerbation2, COPD exacerbation2,cough1

Gastrointestinal disorders Nausea1,2, diarrhoea1, dyspepsia1, dry mouth1,abdominal pain1, vomiting1

Skin and subcutaneous tissue disorders Psoriasiform rash1 or exacerbation of psoriasis1,skin rash1

Musculoskeletal and connective tissue disorders Myalgia1

Reproductive system and breast disorders Sexual dysfunction1, decreased libido1

General disorders and administration site Asthenia1,2conditions

Investigations Liver function tests (LFT) abnormal21 adverse reactions observed with timolol2 adverse reactions observed with bimatoprost

Adverse reactions reported in phosphate containing eye drops

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

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

A topical overdose with GANFORT is not likely to occur or to be associated with toxicity.

Bimatoprost

If GANFORT is accidentally ingested, the following information may be useful: in two-week oral ratand mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This doseexpressed as mg/m2 is at least 70-times higher than the accidental dose of one bottle of GANFORT ina 10 kg child.

Timolol

Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache,dizziness, shortness of breath, and cardiac arrest. A study of patients with renal failure showed thattimolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive.

Pharmacotherapeutic group: Ophthalmologicals - antiglaucoma preparations and miotics - beta-blocking agents - timolol, combinations - ATC code: S01ED51

GANFORT consists of two active substances: bimatoprost and timolol. These two componentsdecrease elevated intraocular pressure (IOP) by complementary mechanisms of action and thecombined effect results in additional IOP reduction compared to either compound administered alone.

GANFORT has a rapid onset of action.

Bimatoprost is a potent ocular hypotensive active substance. It is a synthetic prostamide, structurallyrelated to prostaglandin F2 (PGF2) that does not act through any known prostaglandin receptors.

Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances calledprostamides. The prostamide receptor, however, has not yet been structurally identified.

The mechanism of action by which bimatoprost reduces intraocular pressure in man is by increasingaqueous humour outflow through the trabecular meshwork and enhancing uveoscleral outflow.

Timolol is a beta1 and beta2 non-selective adrenergic receptor blocking agent that does not havesignificant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic(membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. Theprecise mechanism of action is not clearly established, but inhibition of the increased cyclic AMPsynthesis caused by endogenous beta-adrenergic stimulation is probable.

Clinical effects

The IOP-lowering effect of GANFORT is non-inferior to that achieved by adjunctive therapy ofbimatoprost (once daily) and timolol (twice daily).

Existing literature data for GANFORT suggest that evening dosing may be more effective in

IOP-lowering than morning dosing. However, consideration should be given to the likelihood ofcompliance when considering either morning or evening dosing.

The safety and efficacy of GANFORT in children aged 0 to 18 years has not been established.

GANFORT medicinal product

Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing themonotherapy treatments to GANFORT treatment in healthy subjects. Systemic absorption of theindividual components was minimal and not affected by co-administration in a single formulation.

In two 12-month studies where systemic absorption was measured, no accumulation was observedwith either of the individual components.

Bimatoprost

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, thesystemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocularadministration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrationspeaked within 10 minutes after dosing and declined to below the lower limit of detection(0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC 0-24hrs values were similar on days 7and 14 at approximately 0.08 ng/ml and 0.09 ng*hr/ml respectively, indicating that a steady drugconcentration was reached during the first week of ocular dosing.

Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution inhumans at steady-state was 0.67 1/kg. In human blood, bimatoprost resides mainly in the plasma. Theplasma protein binding of bimatoprost is approximately 88%.

Bimatoprost is the major circulating species in the blood once it reaches the systemic circulationfollowing ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation toform a diverse variety of metabolites.

Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administeredto healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. Theelimination half-life, determined after intravenous administration, was approximately 45 minutes; thetotal blood clearance was 1.5 1/hr/kg.

Characteristics in elderly patients

After twice daily dosing, the mean AUC 0-24hrs value of 0.0634 ng*hr/ml bimatoprost in the elderly(subjects 65 years or older) were significantly higher than 0.0218 ng*hr/ml in young healthy adults.

However, this finding is not clinically relevant as systemic exposure for both elderly and youngsubjects remained very low from ocular dosing. There was no accumulation of bimatoprost in theblood over time and the safety profile was similar in elderly and young patients.

Timolol

After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peaktimolol concentration was 898 ng/ml in the aqueous humour at one hour post-dose. Part of the dose isabsorbed systemically where it is extensively metabolised in the liver. The half-life of timolol inplasma is about 4 to 6 hours. Timolol is partially metabolised by the liver with timolol and itsmetabolites excreted by the kidney. Timolol is not extensively bound to plasma.

GANFORT medicinal product

Repeated dose ocular toxicity studies on GANFORT showed no special hazard for humans. The ocularand systemic safety profile of the individual components is well established.

Bimatoprost

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-specificabortion at systemic exposure levels 33- to 97-times that achieved in humans after ocularadministration.

Monkeys administered ocular bimatoprost concentrations of 0.03% daily for 1 year had an increasein iris pigmentation and reversible dose-related periocular effects characterised by a prominent upperand/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears tobe caused by increased stimulation of melanin production in melanocytes and not by an increase inmelanocyte number. No functional or microscopic changes related to the periocular effects have beenobserved, and the mechanism of action for the periocular changes is unknown.

Timolol

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

Sodium chloride

Sodium phosphate dibasic heptahydrate

Citric acid monohydrate

Hydrochloric acid or sodium hydroxide (to adjust pH)

Purified water

Not applicable.

2 years.

Chemical and physical in-use stability has been demonstrated for 28 days at 25°C.

From a microbiological point of view, the in-use storage times and conditions are the responsibility ofthe user and would normally not be longer than 28 days at 25°C.

This medicinal product does not require any special storage conditions.

White opaque low-density polyethylene bottles with polystyrene screw cap. Each bottle has a fillvolume of 3 ml.

The following pack sizes are available: cartons containing 1 or 3 bottles of 3 ml. Not all pack sizesmay be marketed.

No special requirements.

AbbVie Deutschland GmbH & Co. KG

Knollstrasse67061 Ludwigshafen

Germany

EU/1/06/340/001

EU/1/06/340/002

Date of first authorisation 19 May 2006

Date of latest renewal 23 June 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency: https://www.ema.europa.eu/.