Combigan

In section 2 (Qualitative and Quantitative Composition) excipients with known effects were added (phosphates 10.58mg/mL).

In section 4.2 (Posology and method of administration) recommended dosage in adults (including the elderly) was updated.  The recommended dose is one drop of Combigan in the affected eye(s) twice daily, approximately 12 hours apart.

The safety and efficacy of Combigan in children aged 2 to 17 have not been established and therefore, its use is not recommended in children or adolescents (see also section 4.4, section 4.8 and section 4.9). 

Combigan has not been studied in patients with hepatic or renal impairment.  Therefore, caution should be used in treating such patients.

In section 4.4 (Special warnings and precautions for use) the subsection ocular effects was updated to eye disorders.

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. 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.

In section 4.8 (undesirable effects) hallucination was added.

In section 10 (date of revision of the text) the revised date was updated to 04/12/2020.

 

Section 4.2 -    Reformatting of information regarding Paediatric population
                        Additional advice regarding method of administration

Section 4.4 -    Additional information regarding cardiac reactions

Section 4.8 -    Addition of adverse reactions reported in eye drops containing phosphates
                        Addition of information related to the reporting of suspected adverse reactions

4.2  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.

4.3  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.

4.4  Special warnings and precautions for use

4.4

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.



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
1.0	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
4.2	Posology and method of administration	Text edited: To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.
4.5	Interaction with other medicinal products and other forms of interaction	Text edited: No interaction studies have been performed
4.6	Pregnancy and lactation	Text edited: 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.
4.8	Undesirable effects	Deleted text: Brimonidine Vascular disorders: hypotension
5.3	Pre-clinical safety data	Text edited: 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

 

 

Section Number	Subject	Change
4.2	Posology and method of administration	Text edited: Combigan is contraindicated in neonates and infants (less than 2 years of age).   Text edited: 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	Text edited: §           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).
4.8	Undesirable effects	Text edited: 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).   Text deleted: Should be treated with caution and closely monitored due to the high incidence of somnolence.
4.9	Overdose	Text edited: 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.
10	Date of revision of text	Amended to 7th May 2008.

 

Key:

 

Words added within the text are in red and underlined eg (see section 4.3).

 

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

 

 

Section Number	Subject	Change
4.2	Posology and method of administration	Text edited: Combigan is contraindicated in neonates and infants (less than 2 years of age).   Text edited: 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	Text edited: §           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).
4.8	Undesirable effects	Text edited: 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).   Text deleted: Should be treated with caution and closely monitored due to the high incidence of somnolence.
4.9	Overdose	Text edited: 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.
10	Date of revision of text	Amended to 6th May 2008.

 

Key:

 

Words added within the text are in red and underlined eg (see section 4.3).