When a pharmaceutical company changes an SPC or PIL, a new version is published on medicines.ie. For each version, we show the dates it was published on medicines.ie and the reasons for change.
Summary of Changes to ALPHAGAN® IE Summary of Product Characteristics (SPC)
The current ALPHAGAN® SPC is dated 30th September 2010
This supersedes SPC dated 28th February 2008
Section Number
Subject
Change
4.4
Special warning and precautions for use
Text Added/Removed
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 (see section 4.8). Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease. Some (12.7%) patients in clinical trials experienced an ocular allergic type reaction with Alphagan (see section 4.8 for details). If allergic reactions are observed, treatment with Alphagan should be discontinued. Delayed ocular hypersensitivity reactions have been reported with Alphagan 0.2%, with some reported to be associated with an increase in IOP. Alphagan should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans. Alphagan has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients. The preservative in Alphagan, benzalkonium chloride, may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Known to discolour soft contact lenses.
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 (see section 4.8).
Caution should be exercised in treating patients with severe or unstable and uncontrolled cardiovascular disease.
Some (12.7%) patients in clinical trials experienced an ocular allergic type reaction with Alphagan (see section 4.8 for details). If allergic reactions are observed, treatment with Alphagan should be discontinued.
Delayed ocular hypersensitivity reactions have been reported with Alphagan 0.2%, with some reported to be associated with an increase in IOP.
Alphagan should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.
Alphagan has not been studied in patients with hepatic or renal impairment; caution should be used in treating such patients.
The preservative in Alphagan, benzalkonium chloride, may cause eye irritation. Avoid contact with soft contact lenses. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Known to discolour soft contact lenses.
4.5
Interaction with other medicinal products and other forms of interactions
Alphagan 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). Although specific drug interactions studies have not been conducted with Alphagan, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered. No data on the level of circulating catecholamines after Alphagan administration are available. Caution, however, is advised in patients taking medications which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine. After the application of Alphagan, clinically insignificant decreases in blood pressure were noted in some patients. Caution is advised when using drugs such as antihypertensives and/or cardiac glycosides concomitantly with Alphagan. 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).
Alphagan 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).
Although specific drug interactions studies have not been conducted with Alphagan, the possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.
No data on the level of circulating catecholamines after Alphagan administration are available. Caution, however, is advised in patients taking medications which can affect the metabolism and uptake of circulating amines e.g. chlorpromazine, methylphenidate, reserpine.
After the application of Alphagan, clinically insignificant decreases in blood pressure were noted in some patients. Caution is advised when using drugs such as antihypertensives and/or cardiac glycosides concomitantly with Alphagan.
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).
4.8
Undesirable effects
Text Removed/Text Added
The most commonly reported ADRs are oral dryness, ocular hyperaemia and burning/stinging, all occurring in 22 to 25% of patients. They are usually transient and not commonly of a severity requiring discontinuation of treatment. Symptoms of ocular allergic reactions occurred in 12.7% of subjects (causing withdrawal in 11.5% of subjects) in clinical trials with the onset between 3 and 9 months in the majority of patients. Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of undesirable effects: Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from the available data). Cardiac disorders Uncommon: palpitations/arrhythmias (including bradycardia and tachycardia) Nervous system disorders Very common: headache, drowsiness Common: dizziness, abnormal taste Very rare: syncope Eye disorders Very common: - ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritus, foreign body sensation, conjunctival follicles) - blurred vision - allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis Common: - local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing) - photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
The most commonly reported ADRs are oral dryness, ocular hyperaemia and burning/stinging, all occurring in 22 to 25% of patients. They are usually transient and not commonly of a severity requiring discontinuation of treatment.
Symptoms of ocular allergic reactions occurred in 12.7% of subjects (causing withdrawal in 11.5% of subjects) in clinical trials with the onset between 3 and 9 months in the majority of patients.
Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness. The following terminologies have been used in order to classify the occurrence of undesirable effects: Very Common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very rare (<1/10,000), not known (cannot be estimated from the available data).
Cardiac disorders
Uncommon: palpitations/arrhythmias (including bradycardia and tachycardia)
Nervous system disorders
Very common: headache, drowsiness
Common: dizziness, abnormal taste
Very rare: syncope
Eye disorders
Very common:
- ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritus, foreign body sensation, conjunctival follicles) - blurred vision - allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis Common: - local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing) - photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
pruritus, foreign body sensation, conjunctival follicles)
- blurred vision - allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis Common: - local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing) - photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- allergic blepharitis, allergic blepharoconjunctivitis, allergic conjunctivitis, ocular allergic reaction, and follicular conjunctivitis Common: - local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing) - photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
Common:
- local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing) - photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- photophobia - corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- corneal erosion and staining - ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- ocular dryness - conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- conjunctival blanching - abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- abnormal vision - conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- conjunctivitis Very rare: - iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
Very rare:
- iritis (anterior uveitis) - miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
- miosis Respiratory, thoracic and mediastinal disorders Common: upper respiratory symptoms Uncommon: nasal dryness Rare: dyspnoea Gastrointestinal disorders Very common: oral dryness Common: gastrointestinal symptoms Vascular disorders Very rare: hypertension, hypotension General disorders and administration site conditions Very common: fatigue Common: asthenia Immune system disorders Uncommon: systemic allergic reactions Psychiatric disorders Uncommon: depression Very rare: insomnia The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made: Not known: Eye disorders - iridocyclitis (anterior uveitis) - eyelid pruritus Immune systemSkin 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 receiving brimonidine (see section 4.3). In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
Respiratory, thoracic and mediastinal disorders
Common: upper respiratory symptoms
Uncommon: nasal dryness
Rare: dyspnoea
Gastrointestinal disorders
Very common: oral dryness
Common: gastrointestinal symptoms
Vascular disorders
Very rare: hypertension, hypotension
General disorders and administration site conditions
Very common: fatigue
Common: asthenia
Immune system disorders
Uncommon: systemic allergic reactions
Psychiatric disorders
Uncommon: depression
Very rare: insomnia
The following adverse reactions have been identified during post-marketing use of Alphagan in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made:
Not known:
- iridocyclitis (anterior uveitis)
- eyelid pruritus
Immune systemSkin 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 receiving brimonidine (see section 4.3).
In a 3-month, phase 3 study in children aged 2-7 years with glaucoma, inadequately controlled by beta-blockers, a high prevalence of somnolence (55%) was reported with Alphagan as adjunctive treatment. In 8% of children, this was severe and led to discontinuation of treatment in 13%. The incidence of somnolence decreased with increasing age, being least in the 7-year-old age group (25%), but was more affected by weight, occurring more frequently in those children weighing £20 kg (63%) compared to those weighing >20 kg (25%) (see section 4.4).
4.9
Overdose
Ophthalmic overdose (Adults):
There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route. However, symptoms of brimonidine overdose (including loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infants receiving Alphagan as part of medical treatment of congenital glaucoma. In those cases received, the events reported have generally been those already listed as adverse reactions. Systemic overdose resulting from accidental ingestion: Two cases of adverse effects following inadvertent ingestion of 9-10 drops of Alphagan by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of Alphagan orally. 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. Treatment of oral overdose includes supportive and symptomatic therapy; patient’s airways should be maintained. 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.
There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route. However, symptoms of brimonidine overdose (including loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infants receiving Alphagan as part of medical treatment of congenital glaucoma.
In those cases received, the events reported have generally been those already listed
as adverse reactions.
Systemic overdose resulting from accidental ingestion:
Two cases of adverse effects following inadvertent ingestion of 9-10 drops of Alphagan by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of Alphagan orally. 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. Treatment of oral overdose includes supportive and symptomatic therapy; patient’s airways should be maintained. 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.
Two cases of adverse effects following inadvertent ingestion of 9-10 drops of Alphagan by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who also ingested an unknown amount of Alphagan orally.
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.
Treatment of oral overdose includes supportive and symptomatic therapy; patient’s airways should be maintained.
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.
10
DATE OF REVISION OF THE TEXT
Text Removed/Added
02/2008 09/2010
Key:
Unchanged text appears as follows: eg Paediatric population
Added text appears as follows: eg Uveitis
Deleted (Removed) text appears as follows: eg Not applicable
2
Qualitative and quantitative composition
Word “Excipient(s)” inserted before “Contains benzalkonium chloride 0.05 mg/ml.”
Posology and method of administration
Wording change:
Use in children and neonates
Replaced with
Use in paediatric subjects
Following text added:
No clinical studies have been performed in adolescents (12 to 17 years).
Words inserted:
Alphagan is not recommended for use in children below 12 years and is contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4 and 4.9).
4.3
Contraindications
Neonates and infants (see section 4.8)
Special warnings and precautions for use
Text deleted:
Symptoms of brimonidine overdose have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.
Text added:
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 of somnolence (see section 4.8).
4.7
Effects on ability to drive and use machines
The patient should wait until these symptoms have cleared before driving or using machinery.
Punctuation:
a) deleted
Section restructured and summary of “common etc” definitions included at beginning:
New text:
Restructured text:
- ocular irritation including allergic reactions (hyperaemia, burning and stinging, pruritus, foreign body sensation, conjunctival follicles)
- blurred vision
- local irritation (eyelid hyperaemia and oedema, blepharitis, conjunctival oedema and discharge, ocular pain and tearing)
- photophobia
- corneal erosion and staining
- ocular dryness
- conjunctival blanching
- abnormal vision
- conjunctivitis
- iritis (anterior uveitis)
- miosis
c) Symptoms of brimonidine overdose such as hypotension, bradycardia, hypothermia and apnea have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.
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 (see section 4.3).
New information inserted / punctuation amendments
Old Text:
Ophthalmic overdose:
There is no experience in adults with the unlikely case of an overdosage via the ophthalmic route. However, symptoms of brimonidine overdose such as hypotension, bradycardia, hypothermia and apnea have been reported in a few neonates receiving Alphagan as part of medical treatment of congenital glaucoma.
One report of accidental human adult ingestion of Alphagan has been received. The patient ingested about 10 drops of Alphagan. He experienced a hypotensive episode a few hours after the ingestion and then a rebound hypertension approximately 8 hours after ingestion.
Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotonia, hypothermia, respiratory depression and seizure.
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, hypotonia, bradycardia, hypothermia 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.
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
6.1
List of excipients
Hydrochloric acid (for pH-adjustment) or
Sodium hydroxide (for pH-adjustment)
6.3
Shelf Life
After first opening: Use within 28 days.
6.5
Nature and contents of container
Text deleted / added:
White low density polyethylene dropper bottles with a 35 microlitre tip. The cap is either a conventional polystyrene white or purple screw cap or a Compliance Cap (C-Cap).
Date of revision of text
Amended to 28th February 2008
All
® Removed throughout document
Qualitative and Quantitative composition
Text updated
One ml solution contains 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine.
Contains benzalkonium chloride 0.05 mg/ml.
For a full list of excipients, see section 6.1.
Replaces
Brimonidine [(R,R)-tartrate] 0.2% (2.0 mg/ml)
(equivalent to brimonidine base 0.13%, 1.3 mg/ml)
1 drop of Alphaganâ = approximately 35 ml = 70 mg brimonidine tartrate
For excipients, see 6.1.
4.2
Text added
The following heading were added
Recommended dosage in adults
Use in renal and hepatic impairment
Alphagan is not recommended for use in children below 12 years and is contraindicated in neonates (see sections 4.3, 4.4 and 4.9) replaces Alphaganâ should not be used in neonates and is not recommended for use in children (see Section 4.3 Contra-indications; Section 4.4 Special warning and precautions for use and Section 4.9 Overdose).
· Hypersensitivity to the active substance or to any of the excipients.
· Neonates.
· Patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).
Alphaganâ is contraindicated for use in neonates and in patients with hypersensitivity to brimonidine tartrate or any component of this medication. Alphaganâ is also contra-indicated in patients receiving monoamine oxidase (MAO) inhibitor therapy and patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin).
Heading updated (in red)
Avoid contact with soft contact lenses
Heading Eye disorders replaces Ocular effects
Text
Uncommon (>1/1,000 and <1/100): systemic allergic reactions
Uncommon (>1/1,000 and <1/100): depression
Very rare (<1/10,000): insomnia
Very common (>1/10): headache, drowsiness
Common (>1/100 and <1/10): dizziness, abnormal taste
Very rare (<1/10,000): syncope
Uncommon (>1/1,000 and <1/100): palpitations/arrhythmias (including bradycardia and tachycardia)
Very rare (<1/10,000): hypertension, hypotension
Common (>1/100 and <1/10): upper respiratory symptoms
Uncommon (>1/1,000 and <1/100): nasal dryness
Rare (>1/10,000 and <1/1,000): dyspnoea
Very common (>1/10): oral dryness
Common (>1/100 and <1/10): gastrointestinal symptoms
Very common (>1/10): fatigue
Common (>1/100 and <1/10): asthenia
Systemic effects
Very Common:(>1 in 10)
Headache
Oral dryness
Fatigue/drowsiness
Common:(>1 in 100 and <1 in 10)
Upper respiratory symptoms
Dizziness
Gastrointestinal symptoms
Asthenia
Abnormal taste
Uncommon:(>1 in 1,000 and<1 in 100)
Palpitations/arrythmias (including bradycardia and tachycardia)
Systemic allergic reactions
Depression
Nasal dryness
Rare:(>1 in 10,000 and<1 in 1,000)
Dyspnoea
Very Rare:(<1 in 10,000)
Syncope
Hypertension
Hypotension
Insomnia
5.1
Pharmacodynamic properties
Pharmacotherapeutic group: Sympathomimetics in glaucoma therapy
5.3
Preclinical safety data
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction.
The available mutagenicity and carcinogenicity data indicate that Alphaganâ will exert neither mutagenic nor carcinogenic activities under the conditions of clinical use
Poly(vinyl alcohol) replaces Polyvinyl alcohol
Sodium citrate replaces Sodium citrate, dehydrate
Sodium hydroxide for pH adjustment replaces Sodium hydroxide to adjust pH
6.6
Special precautions for disposal of a medicinal product or waste materials derived from such medicinal product and other handling of the product
Heading changed
Special precautions for disposal of a medicinal product or waste materials derived from such medicinal product and other handling of the product replaces Instructions for use and handling
9
Date of first authorization/Renewal of the authorisation
Date of first authorisation: 14 November 1997
Date of last renewal: 17 September 2006
Replaces 14th November 1997/17th March 2002
June 2007 replaces 18th April 2005