Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2020 Publisher: Allergan Pharmaceuticals Ireland, Castlebar Road, Westport, Co. Mayo, Ireland
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.
Combigan has not been studied in patients with closed-angle glaucoma.
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 reactions have been reported including, rarely, death associated with cardiac failure following administration of timolol. 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, beta-blockers should only be given with caution to patients with first degree heart block.
As with systemic beta-blockers, if discontinuation of treatment is needed in patients with coronary heart disease, therapy should be withdrawn gradually to avoid rhythm disorders, myocardial infarct or sudden death.
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 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.
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.
Beta-blockers may also mask the signs of hyperthyroidism.
Combigan must be used with caution in patients with metabolic acidosis and untreated phaeochromocytoma.
Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
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).
While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.
Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g. timolol, acetazolamide) after filtration procedures.
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.
The preservative in Combigan, benzalkonium chloride, may cause eye irritation, symptoms of dry eyes, and may affect the tear film and corneal surface with prolonged use. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Avoid contact with soft contact lenses.
Combigan should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use.
Combigan contains phosphates, which may cause in very rare cases cloudy patches on the cornea due to calcium build-up during treatment.
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 α-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 MAO Inhibitor therapy should wait 14 days after discontinuation before commencing treatment with Combigan.
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.
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.
Studies in animals have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see 5.3).
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 Combigan is administered in pregnancy up to the time of delivery, the neonate should be carefully monitored during the first days of life.
It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat.
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 should not be used by women breast-feeding infants.
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.
Based on 12 month clinical data, the most commonly reported ADRs were conjunctival hyperaemia (approximately 15% of patients) and burning sensation in the eye (approximately 11% of patients). The majority of these cases was mild and led to discontinuation rates of only 3.4% and 0.5% respectively.
The following adverse drug reactions were reported during clinical trials with Combigan:
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).
Very common: conjunctival hyperaemia, burning sensation
Common: 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
Uncommon: visual acuity worsened, conjunctival oedema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment
Common: depression
Common: somnolence, headache
Uncommon: dizziness, syncope
Uncommon: congestive heart failure, palpitations
Common: hypertension
Uncommon: rhinitis, nasal dryness
Common: oral dryness
Uncommon: taste perversion, nausea, diarrhoea
Common: eyelid oedema, eyelid pruritus, eyelid erythema
Uncommon: allergic contact dermatitis
Common: asthenic conditions
The following adverse drug reactions have been reported since Combigan has been marketed:
Not known: vision blurred
Not known: arrhythmia, bradycardia, tachycardia
Not known: hypotension
Not known: erythema facial
Additional adverse events that have been seen with one of the components and may potentially occur also with Combigan:
Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis.
Psychiatric disorders: insomnia.
Respiratory, thoracic and mediastinal disorders: upper respiratory symptoms, dyspnoea.
Gastrointestinal disorders: gastrointestinal symptoms.
General disorders and administration site conditions: systemic allergic reactions.
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, hallucination.
Nervous system disorders: cerebrovascular accident, cerebral ischemia, increases in signed and symptoms of myasthenia gravis, paraesthesia.
Eye disorders: keratitis, choroidal detachment following filtration surgery (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.
Adverse reactions reported in eye drops containing phosphates:
Cases of corneal calcification have been reported very rarely in association with the use of phosphate containing eye drops in some patients with significantly damaged corneas.
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
Not applicable.
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