Timolol/ Brimonidine

Registered South African indications:

• Control of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are stabilised on the individual components given at the same dosages

Registered South African contraindications

• Hypersensitivity to the active substances or to any of the excipients
• The safety and effectiveness in patients less than 18 years of age have not been established
• Reactive airway disease including
  • Bronchospasm
  • Bronchial asthma or a history of bronchial asthma
  • Severe chronic obstructive pulmonary disease
• Sinus bradycardia
• Sick sinus syndrome
• Sino-atrial nodal block
• Second- and third-degree atrioventricular block not controlled with a pacemaker
• Overt cardiac failure
• Cardiogenic shock
• Use in neonates and infants (less than two years of age)
• Patients receiving monoamine oxidase (MAO) inhibitor therapy or within 2 weeks of stopping MAO-inhibitor therapy
• Concomitant use of linezolid
• Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants)

Contraindications registered in other jurisdictions

• Hypersensitivity to the active substances or to any of the excipients
• Reactive airway disease including
  • Bronchial asthma or a history of bronchial asthma
  • Severe chronic obstructive pulmonary disease
• Sinus bradycardia
• Sick sinus syndrome sino-atrial block
• Second- or third-degree atrioventricular block not controlled with a pace-maker
• Overt cardiac failure
• Cardiogenic shock
• Use in neonates and infants (less than 2 years of age)
• Patients receiving monoamine oxidase (MAO) inhibitor therapy
• Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin)

• Pregnancy
• Breastfeeding
• Renal impairment
• Hepatic impairment
• Children
• Cardiovascular disease 
• Abrupt withdrawal in patients with coronary artery disease 
• First degree heart block
• Severe peripheral circulatory disorders
• Asthma 
• Mild to moderate chronic obstructive pulmonary disease
• Risk factors for spontaneous hypoglycaemia 
• Labile diabetes mellitus 
• Metabolic acidosis
• Untreated phaeochromocytoma
• Corneal disease
• History of atopy
• History of severe anaphylactic reaction
• Closed angle glaucoma
• Concomitant use of soft contact lenses
• May impair ability to drive and operate machinery

Forms avail. in SA and covered in this monograph: opd

South African registered indications and dosages

Control of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are stabilised on the individual components given at the same dosages

Timolol/ Brimonidine
5/2 (mg/ml)

• Ophthalmic (opd): 1 drop into affected eye(s), twice daily approx. 12hrs apart

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

To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface. Keep the container tightly closed

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

Contraindicated

Pregnancy

South African recommendations

• Caution; not recommended
• Safety in pregnancy has not been established in controlled clinical studies in pregnant women
• Brimonidine tartrate: Studies in rats have shown reproductive toxicity only at high maternotoxic doses representing an exposure margin 580-times the human exposure after topical ocular timolol/ brimonidine. There was no reproductive toxicity observed in rabbits. 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. No foetal malformations were observed in mice, rats or rabbits at oral doses up to 50mg/kg/day which is 4200-fold the daily dose of timolol/ brimonidine in humans. However, epidemiological studies suggest that a risk of intra uterine growth retardation may exist following exposure to systemic beta-blockers. In addition, some signs and symptoms of beta-blockade (e.g. bradycardia) have been observed in both the foetus and the neonate
• Consequently, timolol/ brimonidine should not be used during pregnancy

Recommendations in other jurisdictions

• Caution; not recommended
• There are no adequate data for the use of the timolol/ brimonidine fixed combination in pregnant women. Timolol/ brimonidine should not be used during pregnancy unless clearly necessary
• Brimonidine tartrate: 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. 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. 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
• If timolol/ brimonidine is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life

Breastfeeding

South African recommendations

• Caution; not recommended
• Safety in lactation has not been established in controlled clinical studies in lactating women
• Timolol/ brimonidine should not be used by women breast-feeding infants
• Brimonidine tartrate: It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat
• Timolol: Beta-blockers are excreted in breast milk

Recommendations in other jurisdictions

• Caution; not recommended
• Timolol/ brimonidine should not be used by women breast-feeding infants
• Brimonidine tartrate: It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat
• 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

Fertility

Recommendations below are applicable to South African and other jurisdictions

• No information available

• Caution; no information available

• Caution; no information available

• No dose adjustment recommended

Central Nervous System Disorders

• Depression
• Somnolence
• Headache
• Dizziness
• Syncope
• Asthenia 
• Insomnia
• Nightmares
• Memory loss
• Cerebrovascular accident
• Cerebral ischemia
• Exacerbation of myasthenia gravis
• Paraesthesia

Cardiovascular Disorders

• Congestive heart failure
• Palpitations
• Hypertension
• Arrhythmia
• Bradycardia
• Tachycardia
• Hypotension
• Chest pain
• Oedema
• Atrioventricular block
• Cardiac arrest
• Cardiac failure
• Raynaud's phenomenon
• Cold hands and feet

Respiratory Disorders

• Rhinitis
• Nasal dryness
• Upper respiratory symptoms
• Dyspnoea
• Bronchospasm 
• Cough

Gastrointestinal Disorders

• Oral dryness
• Taste perversion
• Nausea and vomiting
• Diarrhoea
• Dyspepsia
• Abdominal pain

Genitourinary Disorders

• Sexual dysfunction
• Decreased libido

Endocrine and Metabolic Disorders

• Hypoglycaemia

Musculoskeletal Disorders

• Myalgia

Skin and Subcutaneous Tissue Disorders

• Eyelid oedema
• Eyelid pruritus
• Eyelid erythema
• Allergic contact dermatitis
• Facial erythema 
• Erythema
• Facial oedema
• Pruritus
• Rash
• Vasodilatation
• Alopecia
• Psoriasiform rash 
• Exacerbation of psoriasis
• Skin rash

Immune, Blood and Lymphatic System Disorders

• Systemic allergic reactions
• Anaphylactic reaction

Sensory Disorders

• Conjunctival hyperaemia
• Burning sensation
• Stinging sensation in the eye
• Allergic conjunctivitis
• Corneal erosion
• Superficial punctuate keratitis
• Eye pruritus
• Conjunctival folliculosis
• Visual disturbance
• Blepharitis
• Epiphora
• Eye dryness
• Eye discharge
• Eye pain
• Eye irritation
• Foreign body sensation
• Conjunctival oedema
• Follicular conjunctivitis
• Conjunctivitis
• Vitreous floater
• Asthenopia
• Photophobia
• Papillary hypertrophy
• Eyelid pain
• Conjunctival blanching
• Corneal oedema
• Corneal infiltrates
• Vitreous detachment
• Iritis
• Iridocyclitis
• Miosis
• Keratitis
• Choroidal detachment following filtration sugery
• Decreased corneal sensitivity
• Corneal erosion
• Ptosis
• Diplopia
• Corneal calcification

• Beta blockers
• Monoamine oxidase inhibitors
• Antidepressants which affect noradrenergic transmission
• Tricyclic antidepressants
• Linezolid
• Mianserin
• Central nervous system depressants
• Calcium channel blockers
• Anti-arrhythmics
• Digitalis glycosides
• Parasympathomimetics 
• Guanethidine
• Brimonidine
• Systemic antihypertensives
• Adrenaline 
• Clonidine (withdrawal)
• CYP2D6 inhibitors
• Anaesthetic agents
• Antidiabetic agents 
• Iodine contrast products
• Lidocaine (IV)
• Cimetidine
• Hydralazine
• Chlorpromazine 
• Methylphenidate 
• Reserpine 
• Alpha agonists 
• Alpha blockers 
• Prostamides
• Prostaglandins
• Carbonic anhydrase inhibitors 
• Pilocarpine

None routine

Timolol
Timolol maleate is a non-selective beta-adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic activity. It combines reversibly with the beta-adrenergic receptor, and this inhibits the usual biologic response that would occur with stimulation of that receptor. Timolol maleate reduces elevated and normal intraocular pressure whether or not associated with glaucoma and has little or no effect on accommodation or pupil size. 

Brimonidine
Brimonidine tartrate is a selective alpha-2-adrenergic receptor agonist. Topical administration of brimonidine tartrate decreases intraocular pressure with minimal effect on cardiovascular or pulmonary parameters. It has a rapid onset of action, with peak ocular hypotensive effect seen at two hours post-dosing. Fluorophotometric studies in animals and humans suggest that brimonidine tartrate has a dual mechanism of action by reducing aqueous humour production and increasing uveoscleral outflow. 

COMBINATION PREPARATIONS

Timolol/ Brimonidine

Eye drops (per ml) 5mg/2mg

• Combigan (Allergan) originator