1.1 Posology and method of administration
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.
1.2 Contraindications
§ 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.
1.3 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.
1.4 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
1.5 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.
1.6 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
1.7 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.
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