Ganfort

Section Number

Subject

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1

Name of the medicinal product

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GANFORT 300 micrograms 0.3mg/ml + 5 mg/ml eye drops, solution

2

Qualitative and Quantitative Composition

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

Contains Excipients

Each ml of solution contains 0.05 mg of benzalkonium chloride 0.05 mg/ml.

For a full list of excipients, see section 6.1.

4.1

Therapeutic indications

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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.

4.2

Posology and method administration

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Posology

Recommended dosage in adults (including the elderly)

The recommended dose is one drop of GANFORT in the affected eye(s) once daily, administered in the morning.

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.

If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.

Use in renalRenal and hepatic impairment

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

UsePaediatric population

The safety and efficacy of GANFORT in children and adolescents aged 0 to 18 years has only not been studied in adults and therefore its use is not recommended in children or adolescents 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

4.4

Special warnings and precautions for use

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Like other topically applied ophthalmic agents,medicinal products, the active substances in GANFORT may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed.

Cardiovascular and respiratory

Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-blockers may occur.

Cardiac failure should be adequately controlled before beginning GANFORT therapy. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. Cardiac and respiratory reactions, including death due to bronchospasm in patients with asthma, and, rarely, death in association with cardiac failures have been reported following administration of timolol maleate.

Other beta-blocker related warnings

Beta-blockers may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

Beta-adrenergic blocking agents medicinal products should be administered with caution in patients subject to spontaneous hypoglycemia or to diabetic patients (especially those with labile diabetes) as beta‑blockers may mask the signs and symptoms of acute hypoglycemia.

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

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 skin and increased iris pigmentation since these have been observed during treatment with bimatoprost and GANFORT. Some of these changes may be permanent, and may lead to differences in appearance between the eyes if only one eye is treated. After discontinuation of GANFORT, pigmentation of iris may be permanent. After 12 months treatment with GANFORT, the incidence of iris pigmentation was 0.2%. After 12 months treatment with bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 years treatment.

Cystoid macular oedema has been reported with GANFORT. Therefore, GANFORT should be used with caution in patients with known risk factors for macular oedema (e.g. aphakic patients, pseudophakic patients with a torn posterior lens capsule).

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.

4.5

Interaction with other medicinal products and other forms of interaction

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No interaction studies have been performed.

There is a potential for additive effects resulting in hypotension, and/or marked bradycardia when eye drops containing timolol are administered concomitantly with oral calcium channel blockers, guanethidine, or beta-blocking agentsblockers, anti-arrhythmics, digitalis glycosides or parasympathomimetics.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents medicinal products. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta‑blockers.

4.6

PregnancyFertility, pregnancy and lactation

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Pregnancy

There are no adequate data from the use of GANFORT in pregnant women.

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). 

Consequently, GANFORT should not be used during pregnancy unless clearly necessary.

LactationBreast-feeding

Timolol is excreted in breast milk. 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.

4.7

Effects on ability to drive and use machines

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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 machinerymachines.

4.8

Undesirable effects

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No Ganfort

Summary of the safety profile

The adverse drug reactions (ADRs) specific for GANFORT have been observed reported in clinical studies.  The ADRs have been 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 ADRs 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 ADR 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

The following ADRs adverse reactions were reported during clinical trials with GANFORT (within each frequency grouping, undesirable effects adverse reactions are presented in order of decreasing seriousness):.

Nervous system disorders

Uncommon (≥1/1000 to <1/100): headache

Eye disorders

4.9

Overdose

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No case of A topical overdose has been reported, and with GANFORT is unlikely not likely to occur after ocular administration or 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 are: bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest.  A study of patients showed that timolol did not dialyse readily.

If overdose occurs treatment should be symptomatic and supportive.

5.1

Pharmacodynamics properties

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Pharmacotherapeutic group: Ophthalmological – beta-blocking agents – timolol, combinations, ATC code: S01ED 51 S01ED51

Mechanism of action:

GANFORT consists of two active substances: bimatoprost and timolol maleate. 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 agent active substance.  It is a synthetic prostamide, structurally related to prostaglandin F_2a (PGF_2a) 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).

There are no studies with evening dosing of GANFORT. Morning dosing of GANFORT is therefore recommended to ensure maximal IOP‑lowering effect at the time of the physiological IOP rise. However, if necessary for patient compliance, an evening dosing may be considered. Once‑daily dosing of timolol 0.5% has a rapid onset of maximal effect, corresponding with the time of this rise, and maintains clinically meaningful IOP‑lowering over the 24‑hour period.  Bimatoprost studies show comparable IOP control regardless of morning or evening dosing.

Paediatric population

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

5.2

Pharmacokinetic properties

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GANFORT:medicineal 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.

5.3

Preclinial Safety Data

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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 ³0.03% 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.

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

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Date of first authorisation 19 May 2006

Date of latest renewal 19 May 2011

10

DATE OF REVISION OF THE TEXT

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07/2010 06/2011