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As with any eye drops, to reduce possible systemic absorption, it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) or eyelids are closed for two minutes. This should be performed immediately following the instillation of each drop. This may result in a decrease of systemic side effects and an increase in local activity.
4.4 Special warnings and precautions for use
Children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg, should be treated with caution and closely monitored due to the high incidence and severity of somnolence. The safety and effectiveness of Combigan in children and adolescents (2 to 17 years of age) have not been established (see section 4.2 and section 4.8).
Some patients have experienced ocular allergic type reactions (allergic conjunctivitis and allergic blepharitis) with Combigan in clinical trials. Allergic conjunctivitis was seen in 5.2% of patients. Onset was typically between 3 and 9 months resulting in an overall discontinuation rate of 3.1%. Allergic blepharitis was uncommonly reported (<1%). If allergic reactions are observed, treatment with Combigan should be discontinued.
Delayed ocular hypersensitivity reactions have been reported with brimonidine tartrate ophthalmic solution 0.2%, with some reported to be associated with an increase in IOP.
Like other topically applied ophthalmic agents, Combigan may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. Due to beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents 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:
In 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 the 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, betablockers 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.
Combigan 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-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Hyperthyroidism
Beta-blockers may also mask the signs of hyperthyroidism.
Combigan must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma. Corneal diseases Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution. Other beta-blocking agents The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to 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 allergans and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions. Choroidal detachment Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures. Surgical anaesthesia Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthetist must be informed if the patient is receiving timolol. 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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally 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. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed with the brimonidine timolol fixed combination. Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, after the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special warnings and precautions for use). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.[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. Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan. Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Other beta-blocking agents
The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiated when timolol is given to 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 allergans and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
Choroidal detachment
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures. Surgical anaesthesia Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthetist must be informed if the patient is receiving timolol. 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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally 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. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed with the brimonidine timolol fixed combination. Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, after the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special warnings and precautions for use). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.[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. Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan. Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Surgical anaesthesia
Beta-blocking ophthalmological preparations may block systemic beta-agonist effects e.g. of adrenaline. The anaesthetist must be informed if the patient is receiving timolol.
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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally
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. 4.5 Interaction with other medicinal products and other forms of interaction No interaction studies have been performed with the brimonidine timolol fixed combination. Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, after the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special warnings and precautions for use). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.[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. Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan. Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
No interaction studies have been performed with the brimonidine timolol fixed combination. Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.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, , beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine.Also, after the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using Combigan with systemic antihypertensives. Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special warnings and precautions for use). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.[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. Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan. Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see 4.4 Special warnings and precautions for use).
The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.[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. Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan. Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Concomitant use of a beta-blocker with anaesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4), and therefore the anaesthetist must be informed if the patient is using Combigan.
Caution must be exercised if Combigan is used concomitantly with iodine contrast products or intravenously administered lidocain. Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Cimetidine, hydralazine and alcohol may increase the plasma concentrations of timolol. No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
No data on the level of circulating catecholamines after Combigan administration are available. Caution, however, is advised in patients taking medication which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine . Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Caution[ is advised when initiating (or changing the dose of) a concomitant systemic agent (irrespective of pharmaceutical form) which may interact with a-adrenergic agonists or interfere with their activity i.e. agonists or antagonists of the adrenergic receptor e.g. (isoprenaline, prazosin). Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Although specific drug interactions studies have not been conducted with Combigan, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered. Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Brimonidine is contraindicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenagic transmission (e.g. tricyclic antidepressants and miaserin), (see section 4.3).Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with Combigan. 4.6 Pregnancy and lactation Pregnancy There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Pregnancy
There are no adequate data for the use of the brimonidine timolol fixed combination in pregnant women. Combigan should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Lactation Brimonidine tartrate 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 4.7 Effects on ability to drive and use machines Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery. 4.8 Undesirable effects Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea. Eye disorders:Not known: Vision blurred Skin disorders: Not known: Erythema facial Brimonidine Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis Psychiatric disorders: insomnia Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3). A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4). Timolol Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. 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 Combigan are listed below: Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction Metabolism: Hypogycaemia Psychiatric disorders: Insomnia, nightmares, memory loss Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure Vascular disorders: Raynaud’s phenomenon, cold hands and feet. Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough. Gastrointestinal disorders: dyspepsia, 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: Fatigue 4.9 Overdose Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained. Brimonidine Ophthalmic overdose(Adults): In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion (Adults): There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure. Paediatric population Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours. Timolol Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Lactation
Brimonidine tartrate
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
Combigan has minor influence on the ability to drive and use machines. Combigan may cause transient blurring of vision, visual disturbance, fatigue and/or drowsiness which may impair the ability to drive or operate machines. The patient should wait until these symptoms have cleared before driving or using machinery.
Uncommon (>1/1000, <1/100): taste perversion, nausea, diarrhoea.
Eye disorders:Not known: Vision blurred
Skin disorders:
Not known: Erythema facial
Brimonidine
Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis
Psychiatric disorders: insomnia
Skin and subcutaneous tissue disorders: - Skin reaction including erythema, face oedema, pruritus, rash and vasodilatation
In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3).
A high incidence and severity of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing ≤20 Kg (see section 4.4).
Like other topically applied ophthalmic drugs, Combigan (brimonidine tartrate/ timolol) is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents.
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 Combigan are listed below:
Immune system disorders: Systemic allergic reactions including angioedema, urticaria, localised and generalised rash, pruritis, anaphylactic reaction
Metabolism: Hypogycaemia
Psychiatric disorders: Insomnia, nightmares, memory loss
Nervous system disorders: Cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia
Eye disorders: keratitis, choroidal detachment following filtration sugery (see section 4.4 Special warnings and special precautions for use), decreased corneal sensitivity, corneal erosion, ptosis, diplopia
Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure
Vascular disorders: Raynaud’s phenomenon, cold hands and feet.
Respiratory, thoracic, and mediastinal disorders: Bronchospasm (predominantly in patients with pre-existing bronchospatic disease), dyspnoea, cough.
Gastrointestinal disorders: dyspepsia, 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: Fatigue
Rare reports of overdosage with COMBIGAN® in humans resulted in no adverse outcome. Treatment of an overdose includes supportive and symptomatic therapy; a patient’s airway should be maintained.
Ophthalmic overdose(Adults):
In those cases received, the events reported have generally been those already listed as
adverse reactions.
Systemic overdose resulting from accidental ingestion (Adults):
There is very limited information regarding accidental ingestion of brimonidine in adults. The only adverse event reported to date was hypotension. It was reported that the hypotensive episode was followed by rebound hypertension. Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia, hypothermia, respiratory depression and seizure.
Paediatric population
Reports of serious adverse effects following inadvertent ingestion of Alphagan by paediatric subjects have been published or reported to Allergan. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated.All subjects were reported to have made a full recovery, usually within 6-24 hours.
Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
Summary of Changes to Combigan® Ireland Summary of Product Characteristics (SPC)
The current Combigan® SPC is dated 26 February 2009
This supersedes SPC dated 7 May 2008
Section Number
Subject
Change
Name of the medicinal product
Text edited:
Combigan 2 mg/ml + 5 mg/ml eye drops, solution
2.0
Qualitative and quantitative composition
Text edited: Contains benzalkonium chloride 0.05 mg/ml. For a full list of excipients, see section 6.1
Contains benzalkonium chloride 0.05 mg/ml.
For a full list of excipients, see section 6.1
4.2
Posology and method of administration
To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.
4.5
No interaction studies have been performed
4.6
Pregnancy and lactation
Brimonidine:
There are no adequate data from the use of brimonidine tartrate in pregnant women. Studies in animals have shown reproductive toxicity at high maternotoxic doses (see section 5.3 Preclinical safety data). The potential risk for humans is unknown. Timolol: Studies in animals have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see 5.3). However, epidemiological studies have not revealed malformative effects but have shown a risk for intra uterine growth retardation when beta‑blockers are administered by the oral route. In addition, signs and symptoms of beta‑blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. Therefore, if Combigan is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.
Timolol:
Studies in animals have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see 5.3). However, epidemiological studies have not revealed malformative effects but have shown a risk for intra uterine growth retardation when beta‑blockers are administered by the oral route. In addition, signs and symptoms of beta‑blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. Therefore, if Combigan is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.
4.8
Undesirable effects
Deleted text:
Vascular disorders: hypotension
5.3
Pre-clinical safety data
The ocular and systemic safety profile of the individual components is well established. Pre-Non-clinical data reveal no special hazard for humans based on conventional studies of the individual components in safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenicity studies.
10
Date of revision of the text
26 February 2009
Key:
Words added within the text are in red and underlined eg (see section 4.3).
Words deleted are struck through eg hypotension
Summary of Changes to Combigan® UK Summary of Product Characteristics (SPC)
The current Combigan® SPC is dated May 2008
This supersedes SPC dated February 2006
Combigan is contraindicated in neonates and infants (less than 2 years of age).
The safety and effectiveness of Combigan in children and adolescents (2 to 17 years of age) have not been established and therefore, its use is not recommended in children or adolescents (see also section 4.4 and section 4.8).
4.3
Contraindications
§ Use in neonates and infants (less than 2 years of age) (see section 4.8)
4.4
Special warnings and precautions for use
Text deleted:
In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants receiving brimonidine. Combigan is therefore contraindicated in these subjects (see section 4.3 Contraindications).
Text added:
The safety and effectiveness of Combigan in children and adolescents (2 to 17 years of age) have not been established (see section 4.2 and section 4.8).
In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine (see section 4.3).
A high incidence of somnolence has been reported in children of 2 years of age and above, especially those in the 2-7 age range and/or weighing < 20 Kg (see section 4.4).
Should be treated with caution and closely monitored due to the high incidence of somnolence.
4.9
Overdose
In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose such as loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea have been reported in neonates and infants (less than 2 years of age) receiving brimonidine.
Date of revision of text
Amended to 7th May 2008.
Amended to 6th May 2008.