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Ganfort (bimatoprost / timolol) – Summary of product characteristics - S01ED51

Updated on site: 07-Oct-2017

Medication nameGanfort
ATC CodeS01ED51
Substancebimatoprost / timolol
ManufacturerAllergan Pharmaceuticals Ireland

Article Contents

1.NAME OF THE MEDICINAL PRODUCT

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

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

Excipient with known effect

Each ml of solution contains 0.05 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Eye drops, solution.

Colourless to slightly yellow solution.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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

4.2Posology and method of administration

Posology

Recommended dosage in adults (including older people)

The recommended dose is one drop of GANFORT in the affected eye(s) once daily, administered either 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 of compliance 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 not exceed one drop in the affected eye(s) daily.

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

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

Method of administration

If more than one topical ophthalmic medicinal product is to be used, each one should be instilled at least 5 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.

4.3

Contraindications

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, 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.

4.4 Special warnings and precautions for use

Like other topically applied ophthalmic medicinal products, the active substances (timolol/ bimatoprost) in GANFORT 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 and cardiac failure) and hypotension therapy with beta-blockers should be critically assessed and 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.

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

Beta-adrenergic blocking medicinal products should be administered with caution in patients subject to spontaneous hypoglycemia or to patients with labile diabetes as beta-blockers may mask the signs and 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 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 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 (see section 4.5).

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 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 anaesthesia

β-blocking ophthalmological preparations may block systemic β-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.

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 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 been observed during treatment with bimatoprost and GANFORT. Increased iris pigmentation is likely to 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. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iridial pigmentation are not known. Iris color changes seen with ophthalmic administration of bimatoprost 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 with GANFORT. Therefore, GANFORT should be used with caution in aphakic patients, in 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. Contact lenses must be removed prior to application, with at least a 15-minute 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.

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 been shown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using GANFORT with other prostaglandin analogues should be monitored for changes to their intraocular pressure.

4.5Interaction with other medicinal products and other forms of interaction

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 when ophthalmic beta-blockers solution is administered concomitantly with oral calcium channel blockers, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, anti-arrhythmics (including amiodarone) and digitalis glycosides.

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.

4.6Fertility, pregnancy and lactation

Pregnancy

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

Bimatoprost

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

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. 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 GANFORT is administered until delivery, the neonate should be carefully 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 (see section 5.3).

Breast-feedingTimolol

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 section 4.2.

Bimatoprost

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

Fertility

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

4.7Effects on ability to drive and use machines

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

4.8Undesirable effects

GANFORT

Summary of the safety profile

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

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

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that have been reported during clinical studies with all GANFORT formulations (multi-dose and single-dose) (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness) or in the post-marketing period.

The frequency of possible adverse reactions listed below is defined using the following convention:

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

 

 

Not known

Frequency 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

Insomnia2, nightmare2

 

Nervous system disorders

Common

headache, dizziness2

 

 

Not known

Dysgeusia2

 

Eye disorders

Very common

conjunctival hyperaemia.

 

 

 

 

 

 

Common

punctuate keratitis, corneal

 

 

 

erosion2, burning sensation2,

 

 

 

conjunctival irritation1, eye

 

 

 

pruritus, stinging sensation in

 

 

 

the eye2, foreign body sensation,

 

 

 

dry eye, erythema of eyelid,

 

 

 

eye pain, photophobia, eye

 

 

 

discharge2, visual disturbance2,

 

 

 

eyelid pruritus, visual acuity

 

 

 

worsened2, blepharitis2, eyelid

 

 

 

oedema, eye irritation,

 

 

 

lacrimation increased, growth of

 

 

eyelashes.

 

Uncommon

iritis2, conjunctival oedema2,

 

 

eyelid pain2, abnormal sensation

 

 

in the eye1, asthenopia,

 

 

trichiasis2, iris

 

 

hyperpigmentation2, deepening

 

 

of eyelid sulcus2, eyelid

 

 

retraction2, eyelash

 

 

discolouration (darkening)1.

 

Not known

cystoid macular oedema2, eye

 

 

swelling, vision blurred2

Cardiac disorders

Not known

Bradycardia

Respiratory, thoracic and

Common

Rhinitis2

mediastinal disorders

 

 

 

 

 

 

Uncommon

dyspnoea

 

Not known

bronchospasm (predominantly

 

 

in patients with pre-existing

 

 

bronchospastic disease) 2,

 

 

asthma

Skin and subcutaneous tissue

Common

blepharal pigmentation2,

disorders

 

hirsutism2, skin

 

 

hyperpigmentation (periocular).

 

Not known

Alopecia2

General disorders and

Not known

fatigue

administration site conditions

 

 

1adverse reactions only observed with Ganfort single-dose formulation 2adverse reactions only observed with Ganfort multi-dose formulation

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

Additional adverse reactions that have been seen with either of the active substances (bimatoprost or timolol), 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

 

anaphylaxis1

Metabolism and nutrition disorders

hypoglycaemia1

Psychiatric disorders

depression1, memory loss1

Nervous system disorders

syncope1, cerebrovascular accident1, increase in

 

signs 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 heart

 

failure1, chest pain1, palpitations1, oedema1

Vascular disorders

hypotension1, hypertension2,Raynaud’s

 

phenomenon1, cold hands 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

asthenia1,2

conditions

 

Investigations

liver function tests (LFT) abnormal2

1adverse reactions observed with Timolol monotherapy

2adverse reactions observed with Bimatoprost monotherapy

Adverse reactions reported in phosphate containing eye drops

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

4.9Overdose

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 rat and mouse studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 70-times higher than the accidental dose of one bottle of GANFORT in a 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 that timolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmological,– beta-blocking agents – ATC code: S01ED51

Mechanism of action

GANFORT consists of two active substances: bimatoprost and timolol. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the

combined 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, structurally related to prostaglandin F2 (PGF2 ) that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified. The mechanism of action by which bimatoprost reduces intraocular pressure in man is by increasing aqueous 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 have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis 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 of bimatoprost (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 of compliance when considering either morning or evening dosing.

Paediatric population

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

5.2Pharmacokinetic properties

GANFORT medicinal product

Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to GANFORT treatment in healthy subjects. Systemic absorption of the individual 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 observed with either of the individual components.

Bimatoprost

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked 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 7 and 14 at approximately 0.08 ng/ml and 0.09 ng hr/ml respectively, indicating that a steady drug

concentration was reached during the first week of ocular dosing.

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

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

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

Characteristics in older people

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 young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood 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, peak timolol concentration was 898 ng/ml in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised in the liver. The half-life of timolol in plasma is about 4 to 6 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.

5.3Preclinical safety data

GANFORT medicinal product

Repeated dose ocular toxicity studies on GANFORT showed no special hazard for humans. The ocular and 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 safety pharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-specific abortion at systemic exposure levels 33- to 97-times that achieved in humans after ocular administration.

Monkeys administered ocular bimatoprost concentrations of 0.03% daily for 1 year had an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears to be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects have been observed, 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 safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Benzalkonium chloride

Sodium chloride

Sodium phosphate dibasic heptahydrate

Citric acid monohydrate

Hydrochloric acid or sodium hydroxide (to adjust pH)

Purified water

6.2Incompatibilities

Not applicable.

6.3Shelf life

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 of the user and would normally not be longer than 28 days at 25 C.

6.4Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5Nature and contents of container

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

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

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

Co. Mayo

Ireland

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/06/340/001-002

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation 19 May 2006

Date of latest renewal 23 June 2011

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency: http://www.ema.europa.eu/.

1.NAME OF THE MEDICINAL PRODUCT

GANFORT 0.3 mg/ml + 5 mg/ml eye drops, solution, in single-dose container.

2.QUALITATIVE AND QUANTITATIVE COMPOSITION

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

For the full list of excipients, see section 6.1.

3.PHARMACEUTICAL FORM

Eye drops, solution, in single-dose container.

Colourless to slightly yellow solution.

4.CLINICAL PARTICULARS

4.1Therapeutic indications

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

4.2Posology and method of administration

Posology

Recommended dosage in adults (including older people)

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

Existing literature data for GANFORT (multi-dose formulation) suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing (see section 5.1).

The single-dose container is for single use only; one container is sufficient to treat both eyes. Any unused solution should be discarded immediately after use. 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.

Renal and hepatic impairment

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

Paediatric population

The safety and efficacy of GANFORT single-dose in children aged less than 18 years has not been established. No data are available.

Method of administration

If more than one topical ophthalmic medicinal product is to be used, each one should be instilled at least 5 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.

4.3

Contraindications

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, 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.

4.4 Special warnings and precautions for use

Like other topically applied ophthalmic medicinal products, the active substances (timolol/ bimatoprost) in GANFORT single-dose may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed with GANFORT (multi-dose formulation). Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions (ADRs) 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 and cardiac failure) and receiving hypotension therapy with beta-blockers should be critically assessed and 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 the 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.

GANFORT single-dose 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 medicinal products should be administered with caution in patients subject to spontaneous hypoglycaemia or in patients with labile diabetes as beta-blockers may mask the signs and symptoms of acute hypoglycemia.

Beta-blockers may also mask the signs of hyperthyroidism.

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 is given to 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 (see section 4.5).

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 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 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

In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost eye drops had no adverse reactions on liver function 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, and periorbital skin hyperpigmentation since these have been observed during treatment with GANFORT single-dose. Increased brown iris pigmentation has also been observed during treatment with GANFORT (multi-dose formulation). Increased iris pigmentation is likely to 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 of treatment with GANFORT (multi-dose formulation), the incidence of iris pigmentation was 0.2%. After 12 months of treatment with bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 years of treatment. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iridial pigmentation are not known. Iris color changes seen with ophthalmic administration of bimatoprost 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 with GANFORT (multi-dose formulation). Therefore, GANFORT single-dose should be used with caution in aphakic patients, in 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.

Other conditions

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

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

4.5Interaction with other medicinal products and other forms of interaction

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 when ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, anti-arrhythmics (including amiodarone) and digitalis glycosides.

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.

4.6Fertility, pregnancy and lactation

Pregnancy

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

Bimatoprost

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

Timolol

Epidemiological studies have not revealed malformative effects but have shown 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 GANFORT single-dose is administered until delivery, the neonate should be carefully 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 (see section 5.3).

Breast-feeding

Timolol

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 section 4.2.

Bimatoprost

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

Fertility

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

4.7Effects on ability to drive and use machines

GANFORT single-dose has negligible influence on the ability to drive and use machines. As with any topical ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machines.

4.8Undesirable effects

GANFORT single-dose

Summary of the safety profile

The adverse reactions reported in the clinical study using GANFORT single-dose were limited to those earlier reported for either GANFORT (multi-dose formulation) or for the single active substances bimatoprost or timolol. No new adverse reactions specific for GANFORT single-dose have been observed in clinical studies.

The majority of adverse reactions reported with GANFORT single-dose were ocular, mild in severity and none were serious. Based on a 12-week study of GANFORT single-dose administered once daily, the most commonly reported adverse reaction with GANFORT single-dose was conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in approximately 21% of patients and led to discontinuation in 1.4% of patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that were reported during clinical studies of both GANFORT single-dose and Ganfort multi-dose formulations (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness) or in the post-marketing period.

The frequency of possible adverse reactions listed below is defined using the following convention:

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

 

 

Not known

Frequency 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

Insomnia2, nightmare2

 

Nervous system disorders

Common

headache, dizziness2

 

 

Not known

Dysgeusia2

 

Eye disorders

Very common

conjunctival hyperaemia.

 

 

 

 

 

 

Common

punctuate keratitis, corneal

 

 

 

erosion2, burning sensation2,

 

 

 

conjunctival irritation1, eye

 

 

 

pruritus, stinging sensation in

 

 

 

the eye2, foreign body sensation,

 

 

 

dry eye, erythema of eyelid, eye

 

 

 

pain, photophobia, eye

 

 

 

discharge2, visual disturbance2,

 

 

 

eyelid pruritus, visual acuity

 

 

 

worsened2, blepharitis2, eyelid

 

 

 

oedema, eye irritation,

 

 

 

lacrimation increased, growth of

 

 

 

eyelashes.

 

 

Uncommon

iritis2, conjunctival oedema2,

 

 

 

eyelid pain2, abnormal sensation

 

 

 

in the eye1, asthenopia,

 

 

trichiasis2, iris

 

 

hyperpigmentation2, deepening

 

 

of eyelid sulcus2, eyelid

 

 

retraction2, eyelash

 

 

discolouration (darkening)1.

 

Not known

cystoid macular oedema2, eye

 

 

swelling, vision blurred2

Cardiac disorders

Not known

Bradycardia

Respiratory, thoracic and

Common

Rhinitis2

mediastinal disorders

 

 

 

 

 

 

Uncommon

dyspnoea

 

Not known

bronchospasm (predominantly

 

 

in patients with pre-existing

 

 

bronchospastic disease) 2,

 

 

asthma

Skin and subcutaneous tissue

Common

blepharal pigmentation2,

disorders

 

hirsutism2, skin

 

 

hyperpigmentation (periocular).

 

Not known

Alopecia2

General disorders and

Not known

fatigue

administration site conditions

 

 

1adverse reactions only observed with Ganfort single-dose formulation 2adverse reactions only observed with Ganfort multi-dose formulation

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

Additional adverse reactions that have been seen with either of the active substances (bimatoprost or timolol), 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

 

anaphylaxis1

Metabolism and nutrition disorders

hypoglycaemia1

Psychiatric disorders

depression1, memory loss1

Nervous system disorders

syncope1, cerebrovascular accident1, increase in

 

signs 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 heart

 

failure1, chest pain1, palpitations1, oedema1

Vascular disorders

hypotension1, hypertension2,Raynaud’s

 

phenomenon1, cold hands 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

asthenia1,2

conditions

 

Investigations

liver function tests (LFT) abnormal2

1adverse reactions observed with Timolol monotherapy

2adverse reactions observed with Bimatoprost monotherapy

Adverse reactions reported in phosphate containing eye drops

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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V*.

4.9Overdose

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

Bimatoprost

If GANFORT single-dose is accidentally ingested, the following information may be useful: in 2-week oral mice and rats studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity; this corresponds to a human equivalent dose of 8.1 and 16.2 mg/kg, respectively. These doses are at least 7.5 times higher than the amount of bimatoprost in an accidental dose of the entire contents of a carton of GANFORT single-dose (90 single-dose containers x 0.4 mL; 36 mL) in a 10 kg child [(36 mL*0.3 mg/mL bimatoprost)/10 kg; 1.08 mg/kg].

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 that timolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive.

5.PHARMACOLOGICAL PROPERTIES

5.1Pharmacodynamic properties

Pharmacotherapeutic group: Ophthalmological, beta-blocking agents – ATC code: S01ED51.

Mechanism of action

GANFORT single-dose consists of two active substances: bimatoprost and timolol. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and

the combined effect results in additional IOP reduction compared to either compound administered alone. GANFORT single-dose has a rapid onset of action.

Bimatoprost is a potent ocular hypotensive active substance. It is a synthetic prostamide, structurally related to prostaglandin F2 (PGF2 ) that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified. The mechanism of action by which bimatoprost reduces intraocular pressure in man is by increasing aqueous 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 have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.

Clinical effects

A 12-week (double-masked, randomized, parallel group) clinical study compared the efficacy and safety of GANFORT single-dose with GANFORT (multi-dose formulation) in patients with glaucoma or ocular hypertension. GANFORT single dose achieved noninferior IOP-lowering efficacy to GANFORT (multi-dose formulation): the upper limit of the 95% CI of the between-treatment difference was within the pre-defined 1.5 mm Hg margin at each timepoint evaluated (hours 0, 2, and 8) at week 12 (for the primary analysis), and also at weeks 2 and 6, for mean worse eye IOP change from baseline (worse eye IOP refers to the eye with the higher mean diurnal IOP at baseline). In fact, the upper limit of the 95% CI did not exceed 0.14 mm Hg at week 12.

Both treatment groups showed statistically and clinically significant mean decreases from baseline in worse eye IOP at all follow up timepoints throughout the study (p < 0.001). Mean changes from baseline worse eye IOP ranged from -9.16 to -7.98 mm Hg for GANFORT (single-dose) group, and from -9.03 to -7.72 mm Hg for the GANFORT (multi-dose formulation) group across the 12-week study.

GANFORT single-dose also achieved equivalent IOP-lowering efficacy to GANFORT (multi-dose formulation) in average eye and worse eye IOP at each follow-up timepoint at weeks 2, 6 and 12.

Based on studies of GANFORT (multi-dose formulation), the IOP-lowering effect of GANFORT is non-inferior to that achieved by adjunctive therapy of bimatoprost (once daily) and timolol (twice daily).

Existing literature data for GANFORT (multi-dose formulation) suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing.

Paediatric population

The safety and efficacy of GANFORT single-dose in children aged less than 18 years has not been established.

5.2Pharmacokinetic properties

GANFORT medicinal product

Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to GANFORT (multi-dose formulation) treatment in healthy subjects. Systemic absorption of the individual components was minimal and not affected by co-administration in a single formulation.

In two 12-month studies of GANFORT (multi-dose formulation) in which systemic absorption was measured, no accumulation was observed of either of the individual components.

Bimatoprost

Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked 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 7 and 14 at approximately 0.08 ng/ml and 0.09 ng hr/ml respectively, indicating that a steady drug

concentration was reached during the first week of ocular dosing.

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

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

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

Characteristics in older people

After twice daily dosing of bimatoprost 0.3 mg/ml, 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 young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood 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, peak timolol concentration was 898 ng/ml in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised in the liver. The half-life of timolol in plasma is about 4 to 6 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.

5.3Preclinical safety data

GANFORT medicinal product

Repeated dose ocular toxicity studies of GANFORT (multi-dose formulation) showed no special hazard for humans. The ocular and 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 safety pharmacology, genotoxicity, carcinogenic potential. Studies in rodents produced species-specific abortion at systemic exposure levels 33- to 97-times that achieved in humans after ocular administration.

Monkeys administered ocular bimatoprost concentrations of 0.03% daily for 1 year had an increase in iris pigmentation and reversible dose-related periocular effects characterised by a prominent upper and/or lower sulcus and widening of the palpebral fissure. The increased iris pigmentation appears to

be caused by increased stimulation of melanin production in melanocytes and not by an increase in melanocyte number. No functional or microscopic changes related to the periocular effects have been observed, 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 safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.

6.PHARMACEUTICAL PARTICULARS

6.1List of excipients

Sodium chloride

Sodium phosphate dibasic heptahydrate

Citric acid monohydrate

Hydrochloric acid or sodium hydroxide (to adjust pH)

Purified water

6.2Incompatibilities

Not applicable.

6.3Shelf life

2 years.

Once the pouch is opened, use within 7 days. Discard the opened single-dose container immediately after first use.

6.4Special precautions for storage

This medicinal product does not require any special temperature storage conditions. Keep the single- dose containers in the pouch in order to protect against light and moisture.

6.5Nature and contents of container

Clear, single-dose low density polyethylene (LDPE) containers with a twist-off tab.

Each single-dose container contains 0.4 ml solution.

The following pack sizes are available: cartons containing 5, 30 or 90 single-dose containers; each strip of 5 single-dose containers are packaged in an aluminium foil pouch. Not all pack sizes may be marketed.

6.6Special precautions for disposal

No special requirements.

7.MARKETING AUTHORISATION HOLDER

Allergan Pharmaceuticals Ireland

Castlebar Road

Westport

Co. Mayo

Ireland

8.MARKETING AUTHORISATION NUMBER(S)

EU/1/06/340/003 5 single-dose containers

EU/1/06/340/004 30 single-dose containers

EU/1/06/340/005 90 single-dose containers

9.DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation 19 May 2006

Date of latest renewal 23 June 2011

10.DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines Agency web site: http://www.ema.europa.eu/.

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