When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
The following text has been added/ amended: 4.2 Posology and method of administration
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. § 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. 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. Hypoglycaemia/diabetes 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. 4.5 Interaction 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. 4.6 Fertility, 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. Lactation 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 should not be used by breast-feeding women. Timolol 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 ophthalmic beta‑blockers and may potentially occur also with GANFORT are listed below: System Organ Class Adverse reaction Immune system disorders Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylaxis Metabolism and nutrition disorders Hypoglycaemia Psychiatric disorders Insomnia, depression, nightmares, memory loss Nervous system disorders Syncope, cerebrovascular accident,dizziness, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders Decreased corneal sensitivity, diplopia, ptosis, choroidal detachment following filtration surgery (see section 4.4), keratitis, blurred vision Cardiac disorder Atrioventricular block, cardiac arrest, arrhythmia, bradycardia, cardiac failure, congestive heart failure, chest pain, palpitations, oedema Vascular disorders Hypotension, Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic and mediastinal disorders Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders Dysgeusia, nausea, diarrhoea, dyspepsia, dry mouth, abdominal pain, vomiting Skin and subcutaneous tissue disorders Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash Musculoskeletal and connective tissue disorders Myalgia, Reproductive system and breast disorders Sexual dysfunction, decreased libido General disorders and administration site conditions Asthenia/fatigue
§ 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, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block, not controlled with pace-maker. Overt cardiac failure, cardiogenic shock. 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. Hypoglycaemia/diabetes 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. 4.5 Interaction 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. 4.6 Fertility, 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. Lactation 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 should not be used by breast-feeding women. Timolol 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 ophthalmic beta‑blockers and may potentially occur also with GANFORT are listed below: System Organ Class Adverse reaction Immune system disorders Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylaxis Metabolism and nutrition disorders Hypoglycaemia Psychiatric disorders Insomnia, depression, nightmares, memory loss Nervous system disorders Syncope, cerebrovascular accident,dizziness, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders Decreased corneal sensitivity, diplopia, ptosis, choroidal detachment following filtration surgery (see section 4.4), keratitis, blurred vision Cardiac disorder Atrioventricular block, cardiac arrest, arrhythmia, bradycardia, cardiac failure, congestive heart failure, chest pain, palpitations, oedema Vascular disorders Hypotension, Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic and mediastinal disorders Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders Dysgeusia, nausea, diarrhoea, dyspepsia, dry mouth, abdominal pain, vomiting Skin and subcutaneous tissue disorders Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash Musculoskeletal and connective tissue disorders Myalgia, Reproductive system and breast disorders Sexual dysfunction, decreased libido General disorders and administration site conditions Asthenia/fatigue
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.
Hypoglycaemia/diabetes
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.
4.5 Interaction 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.
4.6 Fertility, 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.
Lactation
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 should not be used by breast-feeding women.
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 ophthalmic beta‑blockers and may potentially occur also with GANFORT are listed below:
System Organ Class
Adverse reaction
Immune system disorders
Systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylaxis
Metabolism and nutrition disorders
Hypoglycaemia
Psychiatric disorders
Insomnia, depression, nightmares, memory loss
Nervous system disorders
Syncope, cerebrovascular accident,dizziness, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia
Eye disorders
Decreased corneal sensitivity, diplopia, ptosis, choroidal detachment following filtration surgery (see section 4.4), keratitis, blurred vision
Cardiac disorder
Atrioventricular block, cardiac arrest, arrhythmia, bradycardia, cardiac failure, congestive heart failure, chest pain, palpitations, oedema
Hypotension, Raynaud’s phenomenon, cold hands and feet.
Respiratory, thoracic and mediastinal disorders
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough.
Gastrointestinal disorders
Dysgeusia, nausea, diarrhoea, dyspepsia, dry mouth, abdominal pain, vomiting
Skin and subcutaneous tissue disorders
Alopecia, psoriasiform rash or exacerbation of psoriasis, skin rash
Musculoskeletal and connective tissue disorders
Myalgia,
Reproductive system and breast disorders
Sexual dysfunction, decreased libido
General disorders and administration site conditions
Asthenia/fatigue
Summary of Changes to GANFORT® Summary of Product Characteristics (SPC)
The current GANFORT® Units SPC is dated 23th June 2011
This supersedes SPC dated 23rd July 2010
Section Number
Subject
Change
1
Name of the medicinal product
Text Removed/Added
GANFORT 300 micrograms 0.3mg/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). 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.
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
Text Added
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
Text Added/Removed
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
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
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.
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.
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-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
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.
There are no adequate data from the use of GANFORT in pregnant women.
No adequate clinical data in exposed pregnancies are available. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section 5.3).
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
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
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 Very common (≥1/10): conjunctival hyperaemia, growth of eyelashes. Common (≥1/100 to <1/10): superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon (≥1/1000 to <1/100): iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known: cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon (≥1/1000 to <1/100): rhinitis Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10): blepharal pigmentation Uncommon (≥1/1000 to <1/100): hirsutism 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 available data System Organ Class Frequency Adverse reaction Nervous system disorders Uncommon Headache Eye disorders Very common conjunctival hyperaemia, growth of eyelashes. Common superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon rhinitis Skin and subcutaneous tissuedisorders Common blepharal pigmentation Uncommon hirsutism Additional adverse events reactions that have been seen with one either of the components active substances (bimatoprost or timolol) and may potentially occur also with GANFORT are listed below: Bimatoprost Infections and infestations: infection (primarily colds and upper respiratory symptoms). Nervous system disorders: dizziness Eye disorders: allergic conjunctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis. Vascular disorders: hypertension. General disorders and administration site condition: asthenia, peripheral oedema. Investigations: liver function tests (LFT) abnormal. System Organ Class Adverse reaction Nervous system disorders dizziness Eye disorders allergic conjunctivitis, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis Vascular disorders hypertension General disorders and administration site condition asthenia Investigations liver function tests (LFT) abnormal Timolol Psychiatric disorders: insomnia, nightmares, decreased libido Nervous system disorders: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis. Ear and labyrinth disorders: tinnitus. Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure. Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth. Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis. Musculoskeletal and connective tissue disorders: systemic lupus erythematosus. Renal and urinary disorders: Peyronie’s disease. General disorders and administration site conditions: oedema, chest pain, fatigue. System Organ Class Adverse reaction Psychiatric disorders insomnia, nightmares, decreased libido Nervous system disorders dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis Ear and labyrinth disorders tinnitus Cardiac disorder heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure Vascular disorders hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders nausea, diarrhoea, dyspepsia, dry mouth Skin and subcutaneous tissue disorders psoriasiform rash or exacerbation of psoriasis Musculoskeletal and connective tissue disorders systemic lupus erythematosus Renal and urinary disorders Peyronie’s disease General disorders and administration site conditions oedema, chest pain, fatigue
Uncommon (≥1/1000 to <1/100): headache
Eye disorders Very common (≥1/10): conjunctival hyperaemia, growth of eyelashes. Common (≥1/100 to <1/10): superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon (≥1/1000 to <1/100): iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known: cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon (≥1/1000 to <1/100): rhinitis Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10): blepharal pigmentation Uncommon (≥1/1000 to <1/100): hirsutism 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 available data System Organ Class Frequency Adverse reaction Nervous system disorders Uncommon Headache Eye disorders Very common conjunctival hyperaemia, growth of eyelashes. Common superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon rhinitis Skin and subcutaneous tissuedisorders Common blepharal pigmentation Uncommon hirsutism Additional adverse events reactions that have been seen with one either of the components active substances (bimatoprost or timolol) and may potentially occur also with GANFORT are listed below: Bimatoprost Infections and infestations: infection (primarily colds and upper respiratory symptoms). Nervous system disorders: dizziness Eye disorders: allergic conjunctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis. Vascular disorders: hypertension. General disorders and administration site condition: asthenia, peripheral oedema. Investigations: liver function tests (LFT) abnormal. System Organ Class Adverse reaction Nervous system disorders dizziness Eye disorders allergic conjunctivitis, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis Vascular disorders hypertension General disorders and administration site condition asthenia Investigations liver function tests (LFT) abnormal Timolol Psychiatric disorders: insomnia, nightmares, decreased libido Nervous system disorders: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis. Ear and labyrinth disorders: tinnitus. Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure. Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth. Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis. Musculoskeletal and connective tissue disorders: systemic lupus erythematosus. Renal and urinary disorders: Peyronie’s disease. General disorders and administration site conditions: oedema, chest pain, fatigue. System Organ Class Adverse reaction Psychiatric disorders insomnia, nightmares, decreased libido Nervous system disorders dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis Ear and labyrinth disorders tinnitus Cardiac disorder heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure Vascular disorders hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders nausea, diarrhoea, dyspepsia, dry mouth Skin and subcutaneous tissue disorders psoriasiform rash or exacerbation of psoriasis Musculoskeletal and connective tissue disorders systemic lupus erythematosus Renal and urinary disorders Peyronie’s disease General disorders and administration site conditions oedema, chest pain, fatigue
Very common (≥1/10): conjunctival hyperaemia, growth of eyelashes.
Common (≥1/100 to <1/10): superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus.
Uncommon (≥1/1000 to <1/100): iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis.
Not known: cystoid macular oedema.
Respiratory, thoracic and mediastinal disorders Uncommon (≥1/1000 to <1/100): rhinitis Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10): blepharal pigmentation Uncommon (≥1/1000 to <1/100): hirsutism 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 available data System Organ Class Frequency Adverse reaction Nervous system disorders Uncommon Headache Eye disorders Very common conjunctival hyperaemia, growth of eyelashes. Common superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon rhinitis Skin and subcutaneous tissuedisorders Common blepharal pigmentation Uncommon hirsutism Additional adverse events reactions that have been seen with one either of the components active substances (bimatoprost or timolol) and may potentially occur also with GANFORT are listed below: Bimatoprost Infections and infestations: infection (primarily colds and upper respiratory symptoms). Nervous system disorders: dizziness Eye disorders: allergic conjunctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis. Vascular disorders: hypertension. General disorders and administration site condition: asthenia, peripheral oedema. Investigations: liver function tests (LFT) abnormal. System Organ Class Adverse reaction Nervous system disorders dizziness Eye disorders allergic conjunctivitis, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis Vascular disorders hypertension General disorders and administration site condition asthenia Investigations liver function tests (LFT) abnormal Timolol Psychiatric disorders: insomnia, nightmares, decreased libido Nervous system disorders: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis. Ear and labyrinth disorders: tinnitus. Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure. Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth. Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis. Musculoskeletal and connective tissue disorders: systemic lupus erythematosus. Renal and urinary disorders: Peyronie’s disease. General disorders and administration site conditions: oedema, chest pain, fatigue. System Organ Class Adverse reaction Psychiatric disorders insomnia, nightmares, decreased libido Nervous system disorders dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis Ear and labyrinth disorders tinnitus Cardiac disorder heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure Vascular disorders hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders nausea, diarrhoea, dyspepsia, dry mouth Skin and subcutaneous tissue disorders psoriasiform rash or exacerbation of psoriasis Musculoskeletal and connective tissue disorders systemic lupus erythematosus Renal and urinary disorders Peyronie’s disease General disorders and administration site conditions oedema, chest pain, fatigue
Uncommon (≥1/1000 to <1/100): rhinitis
Skin and subcutaneous tissue disorders Common (≥1/100 to <1/10): blepharal pigmentation Uncommon (≥1/1000 to <1/100): hirsutism 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 available data System Organ Class Frequency Adverse reaction Nervous system disorders Uncommon Headache Eye disorders Very common conjunctival hyperaemia, growth of eyelashes. Common superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus. Uncommon iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis. Not known cystoid macular oedema. Respiratory, thoracic and mediastinal disorders Uncommon rhinitis Skin and subcutaneous tissuedisorders Common blepharal pigmentation Uncommon hirsutism Additional adverse events reactions that have been seen with one either of the components active substances (bimatoprost or timolol) and may potentially occur also with GANFORT are listed below: Bimatoprost Infections and infestations: infection (primarily colds and upper respiratory symptoms). Nervous system disorders: dizziness Eye disorders: allergic conjunctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis. Vascular disorders: hypertension. General disorders and administration site condition: asthenia, peripheral oedema. Investigations: liver function tests (LFT) abnormal. System Organ Class Adverse reaction Nervous system disorders dizziness Eye disorders allergic conjunctivitis, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis Vascular disorders hypertension General disorders and administration site condition asthenia Investigations liver function tests (LFT) abnormal Timolol Psychiatric disorders: insomnia, nightmares, decreased libido Nervous system disorders: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis. Ear and labyrinth disorders: tinnitus. Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure. Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth. Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis. Musculoskeletal and connective tissue disorders: systemic lupus erythematosus. Renal and urinary disorders: Peyronie’s disease. General disorders and administration site conditions: oedema, chest pain, fatigue. System Organ Class Adverse reaction Psychiatric disorders insomnia, nightmares, decreased libido Nervous system disorders dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia Eye disorders decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis Ear and labyrinth disorders tinnitus Cardiac disorder heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure Vascular disorders hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation. Respiratory, thoracic and mediastinal disorders bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough. Gastrointestinal disorders nausea, diarrhoea, dyspepsia, dry mouth Skin and subcutaneous tissue disorders psoriasiform rash or exacerbation of psoriasis Musculoskeletal and connective tissue disorders systemic lupus erythematosus Renal and urinary disorders Peyronie’s disease General disorders and administration site conditions oedema, chest pain, fatigue
Common (≥1/100 to <1/10): blepharal pigmentation
Uncommon (≥1/1000 to <1/100): hirsutism
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 available data
Frequency
Headache
conjunctival hyperaemia, growth of eyelashes.
superficial punctuate keratitis, corneal erosion, burning sensation, eye pruritus, stinging sensation in the eye, foreign body sensation, eye dryness, eyelid erythema, eye pain, photophobia, eye discharge, visual disturbance, eyelid pruritus.
iritis, eye irritation, conjunctival oedema, blepharitis, epiphora, eyelid oedema, eyelid pain, visual acuity worsened, asthenopia, trichiasis.
cystoid macular oedema.
rhinitis
Skin and subcutaneous tissuedisorders
blepharal pigmentation
hirsutism
Additional adverse events reactions that have been seen with one either of the components active substances (bimatoprost or timolol) and may potentially occur also with GANFORT are listed below:
Infections and infestations: infection (primarily colds and upper respiratory symptoms).
Nervous system disorders: dizziness
Eye disorders: allergic conjunctivitis, cataract, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis.
Vascular disorders: hypertension.
General disorders and administration site condition: asthenia, peripheral oedema.
Investigations: liver function tests (LFT) abnormal.
dizziness
allergic conjunctivitis, eyelash darkening, increased iris pigmentation, blepharospasm, eyelid retraction, retinal haemorrhage, uveitis
hypertension
General disorders and administration site condition
asthenia
Investigations
liver function tests (LFT) abnormal
Psychiatric disorders: insomnia, nightmares, decreased libido
Nervous system disorders: dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia
Eye disorders: decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis.
Ear and labyrinth disorders: tinnitus.
Cardiac disorders: heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure.
Vascular disorders: hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation.
Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough.
Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, dry mouth.
Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis.
Musculoskeletal and connective tissue disorders: systemic lupus erythematosus.
Renal and urinary disorders: Peyronie’s disease.
General disorders and administration site conditions: oedema, chest pain, fatigue.
insomnia, nightmares, decreased libido
dizziness, memory loss, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia
decreased corneal sensitivity, diplopia, ptosis, choroidal detachment (following filtration surgery), refractive changes (due to withdrawal of miotic therapy in some cases), keratitis
Ear and labyrinth disorders
tinnitus
heart block, cardiac arrest, arrhythmia, syncope, bradycardia, cardiac failure, congestive heart failure
hypotension, cerebrovascular accident, claudication, Raynaud’s phenomenon, cold hands and feet, palpitation.
bronchospasm (predominantly in patients with pre-existing bronchospastic disease) dyspnoea, cough.
nausea, diarrhoea, dyspepsia, dry mouth
psoriasiform rash or exacerbation of psoriasis
systemic lupus erythematosus
Renal and urinary disorders
Peyronie’s disease
oedema, chest pain, fatigue
4.9
Overdose
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.
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.
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.
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
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 F2a (PGF2a) 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.
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 F2a (PGF2a) 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.
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.
Paediatric population
The safety and efficacy of GANFORT in children aged 0 to 18 years has not been established.
5.2
Pharmacokinetic properties
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. 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.
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
Preclinial 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 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.
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.
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.
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
Date of first authorisation 19 May 2006
Date of latest renewal 19 May 2011
10
DATE OF REVISION OF THE TEXT
07/2010 06/2011
Key:
Unchanged text appears as follows: eg Paediatric population
Added text appears as follows: eg medicinal product
Deleted (Removed) text appears as follows: eg Not applicable
Summary of Changes to Ganfort Ireland Summary of Product Characteristics (SPC)
The current Ganfort SPC is dated March 2009
This supersedes SPC dated May 2006
Text amended to reflect the fact that CMO has been reported.
Cystoid macular oedema has not been reported with GANFORT, however, it has been uncommonly reported (>0.1% to <1%) following treatment with bimatoprost. 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).
Lower end of ADR groupings changed from > to ≥
Adverse effect added to Ganfort section.
Cystoid macular oedema removed from bimatoprost section of additional adverse events that have been seen with one of the components and may potentially occur also with GANFORT.
Pharmacodynamic properties
Amended from SO1ED 51 to read S01ED 51 (typo)
Date of revision of the text
Amended from 19 May 2006 to 02 March 2009.