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).
Excipients
Each ml of solution contains 0.05 mg of benzalkonium chloride.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Eye drops, solution.
Colourless to slightly yellow solution.
4. Clinical Particulars
4.1 Therapeutic 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.
4.2 Posology And Method Of Administration
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.
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
4.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients.
• Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
• Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock.
4.4 Special Warnings And Precautions For Use
Like other topically applied ophthalmic 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.
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 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
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-blockers, anti-arrhythmics, digitalis glycosides or parasympathomimetics.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic 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 Pregnancy And Lactation
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.
Breast-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
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.
4.8 Undesirable 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
The following adverse reactions were reported during clinical trials with GANFORT (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness).
The frequency of possible adverse reactions listed below is defined using the following convention:
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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:
Bimatoprost
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Timolol
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4.9 Overdose
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 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. Pharmacological Properties
5.1 Pharmacodynamic 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 F2α (PGF2α) 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
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 elderly patients
After twice daily dosing, the mean AUC 0-24hrs value of 0.0634 ng•hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng•hr/ml in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both elderly and 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.
5.3 Preclinical 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
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
6.1 List Of Excipients
Benzalkonium chloride
Sodium chloride
Sodium phosphate dibasic heptahydrate
Citric acid monohydrate
Hydrochloric acid or sodium hydroxide (to adjust pH)
Purified water
6.2 Incompatibilities
Not applicable.
6.3 Shelf 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.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature 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.
6.6 Special Precautions For Disposal And Other Handling
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 19 May 2011
10. Date Of Revision Of The Text
06/2011
Detailed information on this medicinal product is available on the European Medicines Agency web site: http://www.ema.europa.eu/.
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