GANFORT 0,3 mg/ml + 5 mg/ml Collyre sol récip unidose 30unid

Eye drops in solution in single-dose container.

Colourless to slightly yellow solution.

One ml of solution contains 0,3 mg of bimatoprost and 5 mg of timolol (as 6,8 mg of timolol maleate).

Excipients:

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.

Dosage

Recommended posology in adults (including elderly subjects)

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

Literature data on GANFORT (multidose bottle) suggest that evening administration may be more effective than morning administration in lowering IOP. However, the choice to administer GANFORT in the morning or evening should be based on the best potential for adherence (see section Pharmacodynamics).

The single-dose container is for single use; each single-dose container is sufficient to treat both eyes. Any unused product must be discarded immediately after use. If a dose is missed, the next dose should be administered as planned. The dose must not exceed one drop per day in the affected eye or eyes.

Renal or hepatic impairment

GANFORT in single-dose container has not been studied in patients with hepatic impairment or renal impairment. Consequently, it should be used with caution in these patients.

Paediatric population

The safety and efficacy of GANFORT in single-dose container in children aged 0 to 18 years have not been established. No data are available.

Method of administration

When several topical ophthalmic medicinal products are administered concomitantly, each must be administered at an interval of at least 5 minutes.

Performing nasolacrimal occlusion or closing the eyelids for 2 minutes reduces systemic absorption. This practice aims to minimise systemic side effects and promote the local action of the eye drops.

• Hypersensitivity to the active substances or to any of the excipients listed in section Composition.
• Bronchial hyperreactivity, including bronchial asthma or a history of bronchial asthma, and severe chronic obstructive pulmonary disease.
• Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block, not controlled by a pacemaker. Manifest cardiac failure, cardiogenic shock.

As with other topically applied ophthalmic medicinal products, the active substances (timolol/bimatoprost) contained in GANFORT in single-dose container may pass into the systemic circulation. No increase in systemic absorption of each active substance was observed with GANFORT (multidose bottle). Due to the presence of a beta-adrenergic component, timolol, cardiovascular, pulmonary and other adverse reactions similar to those reported with systemic beta-blockers may occur. Systemic adverse reactions after topical ophthalmic administration are lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary artery disease, Prinzmetal's angina or heart failure) and hypotension, treatment with beta-blockers should be thoroughly evaluated and treatment with other active substances should be considered. Patients with cardiovascular diseases should be monitored for signs of worsening of their disease and adverse reactions.

Due to the negative effect on conduction time, beta-blockers should be administered with caution to patients with first-degree heart block.

Vascular disorders

Caution should be exercised when treating patients with severe disturbances/disorders of peripheral circulation (e.g. severe forms of Raynaud's disease or Raynaud's syndrome).

Respiratory disorders

Respiratory reactions, including deaths due to bronchospasm in patients with asthma, have been reported following the administration of certain ophthalmic beta-blockers.

GANFORT in single-dose container 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 inhibitors should be administered with caution in patients prone to spontaneous hypoglycaemia and in patients with unstable diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.

Beta-blockers may also mask the signs of hyperthyroidism.

Corneal diseases

Ophthalmic beta-blockers may cause ocular dryness. Patients with corneal diseases should be treated with caution.

Other beta-blocking agents

The effect on intraocular pressure or the known effects of systemic beta-adrenergic blockade may be potentiated when timolol is administered to patients already receiving a systemic beta-blocking agent. The response of these patients should be closely monitored. The use of two topical beta-blockers is not recommended (see section Interactions).

Anaphylactic reactions

During treatment with beta-blockers, patients with a history of atopy or of severe anaphylactic reaction to various allergens may be more sensitive to repeated exposure to these allergens or refractory to the usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported following administration of treatment to reduce aqueous humour secretion (e.g. timolol, acetazolamide), following a filtration surgical procedure.

Surgical anesthesia

Ophthalmic preparations of beta-blockers may block the systemic beta-agonist effects of adrenaline, for example. The anaesthetist should be informed that the patient is receiving treatment with timolol.

Liver disorders

In patients who had a pre-treatment history of mild liver disease or abnormal levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin, no adverse effects on liver function were reported during 24 months of treatment with bimatoprost. Ocular timolol is not associated with any known adverse effects on liver function.

Eye disorders

Before starting treatment, patients should be informed of the possibility of eyelash growth and periocular skin hyperpigmentation, as observed in patients treated with GANFORT in single-dose container. Increased brown pigmentation of the iris has also been observed in patients treated with GANFORT (multidose vial). Increased brown pigmentation of the iris may be permanent and may result in differences in appearance between the eyes if only one eye is treated. The change in iris pigmentation may be permanent upon discontinuation of GANFORT treatment. After 12 months of treatment with GANFORT (multidose vial), the incidence of change in iris pigmentation was 0,2 %. After 12 months of treatment with an eye drop containing bimatoprost alone, the incidence was 1,5 % and did not increase after 3 years of treatment. The pigmentation change is due to an increase in melanin content in melanocytes rather than an increase in the number of melanocytes. The long-term effects of increased iris pigmentation are not known. Iris colour changes observed with ocular administration of bimatoprost may go unnoticed for several months or several years. Neither iris naevi nor iris freckles appear to be affected by treatment. In some patients, pigmentation of the periorbital tissues has been reported to be reversible.

Cases of macular oedema, including cystoid macular oedema, have been reported with GANFORT (multidose vial). Therefore, GANFORT in single-dose container should be used with caution in aphakic patients, in pseudophakic patients with posterior capsule rupture and in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, inflammatory eye disease or diabetic retinopathy).

GANFORT should be used with caution in patients with active intraocular inflammation (e.g. uveitis) as the inflammation may be exacerbated.

Skin

Eyelash growth may be increased in areas where the GANFORT solution repeatedly contacts the skin surface. It is therefore important to apply GANFORT as directed and to avoid run-off onto the cheek or other skin areas.

Other conditions

GANFORT in single-dose container has not been studied in patients with inflammatory, neovascular, narrow-angle or closed-angle or congenital glaucoma, or in patients with an inflamed eye.

Studies with bimatoprost 0,3 mg/ml in patients with glaucoma or ocular hypertension have shown that administration of more than one daily dose of bimatoprost into the eye may result in a smaller reduction in IOP. Patients using GANFORT with other prostaglandin analogues should be monitored for changes in their intraocular pressure.

No specific interaction study has been performed with the bimatoprost/timolol fixed combination.

Additive effects resulting in hypotension and/or marked bradycardia may occur when an ophthalmic solution containing beta-blockers is administered in combination with oral calcium channel blockers, guanethidine, adrenergic beta-blockers, parasympathomimetics, antiarrhythmics (including amiodarone) and digitalis glucosides.

Potentiation of systemic beta-adrenergic blockade (e.g., reduced heart rate, depression) has been reported during treatment combining a CYP2D6 inhibitor (e.g., quinidine, fluoxetine, paroxetine) and timolol.

Mydriasis due to concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has occasionally been reported.

Pregnancy

There is no relevant data on the use of the fixed combination bimatoprost/timolol in pregnant women. GANFORT in single-dose container should not be used during pregnancy, unless absolutely necessary. To reduce systemic absorption, see section Dosage and administration.

Bimatoprost

There are no relevant clinical data on use in pregnant women. Studies performed in animals have shown reproductive toxicity at high maternotoxic doses (see section Preclinical safety).

Timolol

Epidemiological studies have not shown signs of fetal malformation, but have shown a risk of intrauterine growth retardation following exposure to oral beta-blockers. In addition, signs and symptoms suggestive of beta-adrenergic blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the newborn when beta-blocker treatment was administered until delivery. If GANFORT in single-dose container is administered until delivery, the newborn should be closely monitored during the first days of life. Studies conducted with timolol in animals have shown reproductive toxicity at doses significantly higher than those used in clinical practice (see section Preclinical safety).

Breast-feeding

Timolol

Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol eye drops, it is unlikely that sufficient quantities would be present in breast milk to cause clinical symptoms of beta-blockade in the infant. To reduce systemic absorption, see section Dosage and administration.

Bimatoprost

The passage of bimatoprost into human breast milk is not known, but bimatoprost is excreted in the milk of lactating rats. It is therefore recommended not to use GANFORT in single-dose container in breast-feeding women.

Fertility

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

GANFORT in single-dose container has a negligible effect on the ability to drive and use machines. As with any ophthalmic treatment, if transient blurred vision occurs after instillation, the patient should wait until their vision becomes normal before driving or using machines.

Summary of the safety profile

The adverse reactions observed in the clinical study using GANFORT in single-dose container were limited to those previously reported for GANFORT (multi-dose bottle) or for each of the active substances, bimatoprost or timolol, taken separately. No other adverse reaction specific to GANFORT single-dose was observed in the clinical studies.

Most adverse reactions observed with GANFORT in single-dose container were ocular and of mild intensity, and none was classified as serious. Based on clinical data obtained during a 12-week study of GANFORT in single-dose container administered once daily, the adverse reaction most frequently reported with GANFORT in single-dose container is conjunctival hyperaemia (generally minimal to mild and considered non-inflammatory), which occurred in approximately 21% of patients and led to treatment discontinuation in 1,4% of patients.

Tabulated list of adverse reactions

Table 1 presents the adverse reactions that have been reported with all presentations of GANFORT (multi-dose bottle and single-dose container) during clinical studies or after marketing.

Possible adverse reactions are listed by MedDRA system organ class and are based on 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); and frequency not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: List of adverse reactions of all presentations of GANFORT (multi-dose bottle and single-dose container)

System organ class	Frequency	Adverse reaction
Immune system disorders	Frequency not known	Hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, ocular allergy
Psychiatric disorders	Frequency not known	Insomnia2, nightmares2
Nervous system disorders	Common	Headache
	Frequency not known	Dysgeusia2, vertigo
Eye disorders	Very common	Conjunctival hyperaemia
	Common	Punctate keratitis, corneal erosion2, burning sensation2, conjunctival irritation1, ocular pruritus, stinging sensation in the eye2, foreign body sensation, dry eye, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbances2, eyelid pruritus, decreased visual acuity2, blepharitis2, eyelid oedema, eye irritation, increased tear secretion, eyelash growth
	Uncommon	Iritis2, conjunctival oedema2, eyelid pain2, abnormal sensation in the eye1, asthenopia, trichiasis2, iris hyperpigmentation2, periorbital and eyelid changes associated with periorbital fat atrophy and skin tension resulting in deepening of the eyelid sulcus, blepharoptosis, enophthalmos, lagophthalmos and eyelid retraction1&2, alteration of eyelash colour (darkening)1
	Frequency not known	Cystoid macular oedema2, eye swelling, blurred vision2, ocular discomfort
Cardiac disorders	Frequency not known	Bradycardia
Vascular disorders	Frequency not known	Hypertension
Respiratory, thoracic and mediastinal disorders	Common	Rhinitis2
	Uncommon	Dyspnoea
	Frequency not known	Bronchospasm (especially in patients with pre-existing bronchospastic disease)2, asthma
Skin and subcutaneous tissue disorders	Common	Eyelid pigmentation2, hirsutism2, cutaneous (periocular) hyperpigmentation
	Frequency not known	Alopecia, skin discolouration (periocular)
General disorders and administration site conditions	Frequency not known	Fatigue

¹ Adverse reactions observed only with GANFORT in single-dose container.

² Adverse reactions observed only with GANFORT in multidose bottle.

As is the case with other topical ophthalmic products, GANFORT (bimatoprost/timolol) can pass into the systemic circulation. Absorption of timolol may cause adverse reactions similar to those observed with systemic beta-blockers. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than after systemic administration. To reduce systemic absorption, see section Dosage and administration.

Other adverse reactions that have been reported with either of the two active substances (bimatoprost or timolol), and which may therefore be observed with GANFORT, are listed below in table 2:

Table 2: List of additional adverse reactions observed with either active substance (bimatoprost or timolol)

System organ class	Adverse reaction
Immune system disorders	Systemic allergic reactions including anaphylaxis1
Metabolism and nutrition disorders	Hypoglycaemia1
Psychiatric disorders	Depression1, memory loss1, hallucination1
Nervous system disorders	Syncope1, cerebrovascular accident1, worsening of signs and symptoms of myasthenia gravis1, paraesthesia1, cerebral ischaemia1
Eye disorders	Decreased corneal sensitivity1, diplopia1, ptosis1, choroidal detachment after filtering surgery (see section Warnings and precautions)1, keratitis1, blepharospasm2, retinal haemorrhage2, uveitis2
Cardiac disorders	Atrioventricular block1, cardiac arrest1, arrhythmias1, heart failure1, congestive heart failure1, chest pain1, palpitations1, oedema1
Vascular disorders	Hypotension1, Raynaud's phenomenon1, coldness of 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 eruption1 or worsening of psoriasis1, skin rash1
Musculoskeletal and connective tissue disorders	Myalgia1
Disorders of the reproductive system and breast	Sexual dysfunction1, decreased libido1
General disorders and administration site conditions	Asthenia1,2
Investigations	Abnormalities in liver function tests2

¹ Adverse effects observed with timolol.

² Adverse effects observed with bimatoprost.

Adverse effects reported with eye drops containing phosphate

Very rarely, cases of corneal calcification have been reported with the use of phosphate-containing eye drops in some patients with significant corneal damage.

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-see Appendix V*.

A topical overdose of GANFORT single-dose container is unlikely to occur or be associated with toxicity.

Bimatoprost

If GANFORT single-dose container is accidentally ingested, the following information may be useful: in two-week oral studies in mice and rats, doses of bimatoprost up to 100 mg/kg/day caused no toxicity; the corresponding equivalent doses for humans are 8,1 and 16,2 mg/kg respectively. These doses are at least 7,5 times higher than the amount of bimatoprost from accidental ingestion of the entire contents of one GANFORT single-dose container box (90 single-dose containers x 0,4 mL, i.e. 36 mL) in a child weighing 10 kg [(36 mL * 0,3 mg/mL bimatoprost)/10 kg, i.e. 1,08 mg/kg].

Timolol

Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath and cardiac arrest. A study in patients with renal impairment indicated that timolol is not readily removed by dialysis.

In case of overdose, symptomatic and supportive treatment should be instituted.

Pharmacotherapeutic class: Ophthalmology - antiglaucoma preparations and miotics - beta-blocking agents - timolol in combination - ATC code: S01ED51.

Mechanism of action

GANFORT single-dose container contains two active substances: bimatoprost and timolol. These two components lower elevated intraocular pressure (IOP) through complementary mechanisms of action, and their combined effect results in an additional reduction in IOP compared with that induced by either compound alone as monotherapy. GANFORT single-dose container has a rapid onset of action.

Bimatoprost is a potent ocular hypotensive active substance. It is a synthetic prostamide, structurally related to prostaglandin F_2α (PGF_2α) which does not act through known prostaglandin receptors. Bimatoprost selectively reproduces the effects of newly discovered biosynthetic substances called prostamides. However, the structure of prostamide receptors has not yet been identified. Bimatoprost reduces intraocular pressure in humans by increasing aqueous humour outflow through the trabecular meshwork and by improving uveoscleral outflow.

Timolol is a non-selective beta₁- and beta₂-adrenergic agent that has no significant intrinsic sympathomimetic activity, no direct depressant action on the myocardium and no local anaesthetic effect (membrane-stabilising activity). Timolol lowers IOP by reducing aqueous humour formation. Its exact mechanism of action is not clearly elucidated, but it is likely to involve inhibition of the increase in cyclic AMP synthesis induced by endogenous beta-adrenergic stimulation.

Clinical effects

A clinical study of 12 weeks (double-blind, randomised, parallel-group) compared the efficacy and safety of GANFORT single-dose container and GANFORT (multidose bottle) in patients with glaucoma or ocular hypertension. GANFORT single-dose container was shown to be non-inferior to GANFORT (multidose bottle) in terms of IOP reduction efficacy: the upper limit of the 95% CI of the difference between treatments was within the previously defined margin of 1,5 mm Hg at each evaluated time point (hours 0, 2 and 8) at week 12 (for the primary analysis) as well as at weeks 2 and 6, regarding the mean change in IOP of the worse eye from baseline (the worse eye is the one with the highest mean diurnal IOP at study start). In fact, the upper limit of the 95% CI did not exceed 0,14 mm Hg at week 12.

Both treatment groups showed, compared with baseline, a statistically and clinically significant mean reduction in IOP of the worse eye at all time points throughout follow-up (p < 0,001). Mean reductions in IOP of the worse eye from baseline ranged from -9,16 to -7,98 mm Hg in the GANFORT (single-dose container) group and from -9,03 to -7,72 mm Hg in the GANFORT (multidose bottle) group throughout the 12-week follow-up.

GANFORT single-dose container also demonstrated efficacy equivalent to that of GANFORT (multidose bottle) in reducing mean IOP in both eyes and IOP of the worse eye at each time point throughout follow-up at weeks 2, 6 and 12.

Based on studies of GANFORT (multidose bottle), the IOP reduction produced by GANFORT is not inferior to that observed with a regimen combining bimatoprost (once daily) and timolol (twice daily).

Literature data on GANFORT (multidose bottle) suggest that evening administration may be more effective than morning administration in lowering IOP. However, the choice of administering GANFORT in the morning or evening should be based on the best potential for adherence.

Paediatric population

The safety and efficacy of GANFORT single-dose container in children aged 0 to 18 years have not been established.

GANFORT medicinal product

Plasma concentrations of bimatoprost and timolol were measured in a crossover study in healthy subjects comparing the effects of these two monotherapies with those of GANFORT (multidose bottle). Systemic absorption of each active substance was minimal; it was not modified for the combination.

No accumulation of either active substance was demonstrated during the two 12-month studies of GANFORT (multidose bottle) in which systemic absorption was measured.

Bimatoprost

Bimatoprost penetrates well into the human cornea and sclera in vitro. After ophthalmic administration, systemic exposure to bimatoprost is very low. No accumulation is observed over time. After repeated administration for two weeks of one drop per day of bimatoprost 0,03 % in both eyes, the plasma peak is obtained 10 minutes after instillation. Circulating plasma concentrations fall below the limit of detection (0,025 ng/ml) after approximately 1 hour 30 after instillation. The mean values of the C_max and of ASC_{0-24 h} (area under the curve) were comparable to those on day 7^th day and to day 14^th day, respectively approximately 0,08 ng/ml and 0,09 ng • h/ml, indicating that a stable drug concentration is reached during the first week of treatment.

Bimatoprost is moderately distributed in body tissues, and the systemic volume of distribution is 0,67 l/kg at steady state in humans. In human blood, bimatoprost is found mainly in plasma. Plasma protein binding is approximately 88 %.

Unchanged bimatoprost is the predominant entity in systemic circulation after ocular administration. Bimatoprost undergoes oxidative metabolism (N-deethylation and glucuronidation) leading to the formation of various metabolites.

Bimatoprost is mainly eliminated by renal excretion. In healthy volunteers, 67 % of an intravenously administered dose is eliminated in the urine and 25 % is excreted in the feces.

The elimination half-life determined after intravenous administration is approximately 45 minutes; the total blood clearance is 1,5 l/h/kg.

Characteristics in elderly patients

When administered at the rate of 2 instillations per day of bimatoprost 0,3 mg/ml, the systemic exposure to bimatoprost observed in subjects older than 65 years (AUC_{0-24 h} : 0,0634 ng•h/ml) is markedly higher than that observed in young adults (AUC_{0-24 h} : 0,0218 ng•h/ml).

However, due to the low systemic passage by the ocular route, this systemic exposure to bimatoprost remains low and without clinical relevance, both in elderly and in young subjects. Given the absence of accumulation of bimatoprost in the blood, the safety profile is comparable in elderly and young patients.

Timolol

Timolol concentrations peak at 898 ng/ml in the aqueous humor one hour after ocular administration of an eye drop solution at 0,5 % in subjects undergoing cataract surgery. Part of the dose passes into the systemic circulation and undergoes significant hepatic metabolism. The plasma half-life of timolol is on the order of 4 to 6 hours. Timolol is partially metabolized in the liver and excreted with its metabolites by the kidneys. The degree of binding of timolol to plasma proteins is low.

GANFORT medicinal product

Toxicity studies of GANFORT (multidose bottle) with repeated ocular administration revealed no particular risk for humans. The ocular and systemic safety profile of each active substance is well established.

Bimatoprost

Non-clinical data from conventional safety pharmacology, genotoxicity and carcinogenicity studies revealed no particular risk for humans. In rodent studies, species-specific abortions were observed at systemic exposure levels 33 to 97 times higher than those achieved in humans after ocular instillation.

In monkeys, daily ocular administration of bimatoprost at concentrations ≥ 0,03% for one year resulted in increased iris pigmentation and reversible, dose-dependent periocular changes characterised by prominence of the upper and/or lower fornices and widening of the palpebral fissure. The process of increased iris pigmentation appears to be due to increased stimulation of melanin production in melanocytes rather than an increase in the number of melanocytes. No functional or microscopic changes related to these periocular effects were observed. The mechanism underlying these periocular effects is unknown.

Timolol

Non-clinical data from conventional safety pharmacology, repeated-dose toxicology, genotoxicity, carcinogenicity and reproductive toxicity studies revealed no particular risk for humans.

2 years.

Once the single-dose container is removed from the sachet, use it within 7 days. All single-dose containers must be kept in the sachet and discarded 10 days after opening the sachet.

No special precautions for storage regarding temperature. Store the single-dose containers in the sachet and return the sachet to the carton, protected from light and moisture.

No special requirements.

List I

Marketing authorisation (AMM)

EU/1/06/340/004 ; CIP 3400927561627 (30unid).

Price:

8,43 euros (30unid).

Social security reimbursement at 65% under the indications:

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree

Collection.