Active ingredients: Brimonidina (Brimonidina tartrato), Timolol
COMBIGAN® 2mg / ml + 5 mg / ml eye drops, solution
Indications Why is Combigan used? What is it for?
COMBIGAN is an eye drop used for the control of glaucoma. It contains two different active ingredients, brimonidine and timolol: both reduce the high pressure inside the eye. Brimonidine belongs to a group of medicines called alpha-2-adrenergic receptor agonists. Timolol belongs to a group of medicines called beta-blockers. COMBIGAN is prescribed to reduce high pressure in the eye when beta-blocker eye drops alone are not enough.
The eye contains a clear aqueous liquid that helps transport the eye's nutrients. This liquid is constantly being eliminated from the eye and new liquid is produced to replace the eliminated one. If the liquid is eliminated too slowly, the pressure inside the eye increases and over time can damage vision. COMBIGAN works by reducing the formation of liquid and increasing the amount of liquid that is eliminated. This reduces the pressure inside the eye while maintaining the nutrient transport function for the eye.
Contraindications When Combigan should not be used
Do not use COMBIGAN eye drops, solution:
- if you are allergic (hypersensitive) to brimonidine tartrate, thymol, beta blockers or any of the other ingredients of this medicine. Symptoms of an allergic reaction may include swelling of the face, lips and throat, wheezing, feeling faint, shortness of breath, itching or redness around the eye.
- if you have or have suffered from breathing problems such as asthma or if you have severe chronic obstructive pulmonary disease (severe lung disease which can cause breathlessness, difficulty in breathing and / or persistent cough)
- if you have heart problems, such as slow heart rate, heart failure or disturbed heart beat (unless controlled by a pacemaker)
- if you are taking monoamine oxidase (MAO) inhibitors or other antidepressant medicines.
COMBIGAN should not be used in children under 2 years of age and usually in children between 2 and 17 years of age.
If you think any of the above points apply to you, do not use COMBIGAN until you have consulted your doctor again.
For those who carry out sporting activities: the use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Precautions for use What you need to know before taking Combigan
Talk to your doctor before using COMBIGAN
- if you have or have had:
- heart disease caused by coronary heart problems (symptoms may include chest pain or tension, breathlessness or choking), heart failure, low blood pressure
- heart rate disturbances, such as slow heart rate
- breathing problems, asthma or chronic obstructive pulmonary disease
- conditions due to impaired blood circulation (such as Raynaud's disease or Raynaud's syndrome)
- diabetes as timolol can mask the signs and symptoms of low blood sugar
- excessive activity of the thyroid gland as timolol can mask the signs and symptoms of thyroid disease
- liver or kidney problems
- adrenal gland tumor
- operative interventions of the eye in order to reduce the pressure of the eye
- if you have or have suffered from allergies (for example, hay fever, eczema) or a severe allergic reaction, you should be aware that the usual dose of adrenaline used to control a severe reaction may need to be increased.
- Before undergoing surgery, tell your doctor that you are using COMBIGAN, as timolol can alter the effects of some drugs used during anesthesia.
Interactions Which drugs or foods can change the effect of Combigan
COMBIGAN can affect or be affected by other medicines you are taking, including other eye drops for the treatment of glaucoma. Tell your doctor or pharmacist if you are taking, have recently taken or might take any other medicines, including medicines for any ailment, even if not related to your eye disorder, including those obtained without a prescription. There are medicines that can interfere with COMBIGAN, so it is especially important that you tell your doctor if you are taking:
- pain relievers
- medicines for insomnia or anxiety
- medicines to treat high blood pressure (hypertension)
- medicines for heart problems (e.g. irregular heartbeat) such as beta blockers, digoxin or quinidine (used to treat heart conditions and some types of malaria)
- medicines to treat diabetes or to control blood sugar
- medicines for depression such as fluoxetine and paroxetine
- other eye drops used to lower high pressure in the eye (glaucoma)
- medicines to treat severe allergic reactions
- medicines that affect hormones, such as adrenaline and dopamine
- medicines that affect the vascular muscles
- medicines to treat heartburn or stomach ulcers.
If you have changed the dosage of any of the medicines you are currently taking or if you regularly use alcohol, please tell your doctor.
If you need anesthetic, tell your doctor or dentist that you are using COMBIGAN.
Warnings It is important to know that:
Pregnancy and breastfeeding
If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a baby, ask your doctor or pharmacist for advice before using this medicine.
Do not use COMBIGAN if you are pregnant unless your doctor considers it necessary.
Do not use COMBIGAN if you are breastfeeding. Timolol can pass into milk. Ask your doctor for advice before taking any medicine while breastfeeding.
Driving and using machines
In some patients COMBIGAN may cause drowsiness, tiredness or blurred vision. Do not drive or use machines until the symptoms have disappeared. If you have any other problems, please report them to your doctor.
Important information about some of the ingredients of COMBIGAN Contact lenses
- Do not use COMBIGAN when wearing contact lenses. Wait at least 15 minutes after taking COMBIGAN before putting your lenses back in.
- A preservative (benzalkonium chloride) present in COMBIGAN can cause eye irritation and is also known to discolor soft contact lenses.
Dosage and method of use How to use Combigan: Dosage
Always use this medicine exactly as your doctor has told you. If in doubt, consult your doctor or pharmacist. COMBIGAN should not be given to children under 2 years of age. The use of COMBIGAN is not recommended in children and adolescents (2 to 17 years of age).
The recommended dose is one drop of COMBIGAN twice a day approximately 12 hours apart. Do not change the dose or stop applying the product without consulting your doctor.
If you use COMBIGAN with other eye drops, leave at least 5 minutes between taking COMBIGAN and taking the other eye drops.
Instructions for Use
Do not use the bottle if the guarantee seal on the cap is not intact before use.
Wash your hands before opening the bottle. You put your head back and look up.
- Slowly the lower eyelid so as to form a small pocket.
- Turn the bottle upside down and apply gentle pressure to release one drop of eye drops for each eye to be treated.
- Release your lower lid and keep your eye closed.
- Keep your eye closed and press your index finger against the corner of the eye (the side where the eye meets the nose) for two minutes. This will help prevent COMBIGAN from going into the rest of your body.
If the drop does not enter the eye, repeat the operation.
To avoid contamination, the tip of the bottle should not touch your eye or come into contact with any other surface. After using the medicine, close the bottle tightly by screwing the cap back on.
If you forget to use COMBIGAN
If you forget to use COMBIGAN, as soon as you remember, put a single drop in the eye to be treated and then return to the normal dosing times. Do not use a double dose to make up for a forgotten dose.
If you stop taking COMBIGAN
For it to work properly, COMBIGAN must be used every day.
If you have any further questions on the use of COMBIGAN, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Combigan
Adults
If you have instilled more COMBIGAN than you should, this is unlikely to cause serious consequences. Give your next dose at the usual time. If this worries you, consult your doctor or pharmacist.
Babies and Children
There have been several reports of overdose in infants and children who have taken brimonidine (one of the active substances in COMBIGAN) as part of the medical treatment of glaucoma. Symptoms of overdose include: sleepiness, sluggishness, low body temperature, paleness and breathing difficulties If any of these side effects occur, contact your doctor immediately.
Adults and children
If COMBIGAN has been accidentally swallowed, contact your doctor immediately.
Side Effects What are the side effects of Combigan
Like all medicines, this medicine can cause side effects, although not everybody gets them.
If you experience any of the following side effects, contact your doctor immediately:
- Heart failure (e.g. chest pain) or irregular heartbeat
- Increase or decrease in heart rate or decrease in blood pressure
Eye disorders
Very common (may affect more than 1 in 10 people):
- Redness of the eye or burning
Common (may affect up to 1 in 10 people):
- Sensation of stinging or pain in the eye
- Allergic reaction in the eye or on the skin around the eye
- Small cracks in the surface of the eye (with or without inflammation)
- Swelling, redness and inflammation of the eyelid
- Irritation or foreign body sensation in the eye
- Itching of the eye and eyelid
- Follicles or white dots on the visual layer that covers the surface of the eye
- Visual disturbances
- Tearing
- Dry eye
- Sticky eyes
Uncommon (may affect up to 1 in 100 people):
- Difficulty in seeing clearly
- Swelling or inflammation of the visual layer that covers the surface of the eye
- Tired eyes
- Sensitivity to light
- Pain in the eyelid
- Whitening of the visual layer that covers the surface of the eye
- Swelling or areas of inflammation under the surface of the eye
- Floating shapes in front of the eyes
Not known (frequency cannot be estimated from the available data):
- blurred vision
Disorders on the body:
Common (may affect up to 1 in 10 people):
- High blood pressure
- Depression
- Drowsiness
- Headache
- Dry mouth
- General weakness
Uncommon (may affect up to 1 in 100 people):
- Heart failure
- Irregular heartbeat
- Feeling lightheaded
- Feeling faint
- Nasal dryness
- Alteration of taste
- Nausea
- Diarrhea
Not known (frequency cannot be estimated from the available data):
- Increased or slowed heart rate
- Low blood pressure
- Redness of the face
Some of these effects may be due to an allergy to any of the components.
Additional side effects have been seen in patients using eye drops containing brimonidine or timolol and are therefore likely to also occur with COMBIGAN.
The following additional side effects have been observed with the use of brimonidine:
- inflammation inside the eye, narrowing of the pupils, insomnia, feeling cold, shortness of breath, symptoms involving the stomach and digestion, generalized allergic reactions, skin reactions including redness, swelling of the face, itchy rash and widening of the vessels sanguine.
Like other drugs applied to the eye, COMBIGAN (brimonidine / timolol) is absorbed into the blood. Absorption of timolol, the beta blocker component of COMBIGAN, may cause undesirable effects similar to those seen with "intravenous" and / or "oral" beta-blockers. The incidence of undesirable effects after topical ophthalmic administration is lower than that resulting from the administration of medicines, for example, by mouth or by injection.
The listed side effects include reactions seen with the class of beta-blockers used to treat eye diseases:
- Generalized allergic reactions including swelling under the skin (which can occur in areas such as the face and limbs and can block the airways, which can cause difficulty in swallowing or breathing), hives (or itchy rash), rash localized and generalized, itching, sudden severe allergic reaction which is life threatening
- Low blood glucose levels
- Sleep disturbances (insomnia), nightmares, memory loss
- Stroke, reduced blood flow to the brain, increased signs and symptoms of myasthenia gravis (muscle disorders), unusual sensations (such as tingling or numbness)
- Inflammation in the cornea, detachment of the layer under the retina that contains blood vessels following filter surgery which can cause visual disturbances, decreased corneal sensitivity, corneal erosion (damage to the frontal layer of the eyeball), drooping of the upper eyelid (which produces closing half of the eye), double vision
- Chest pain, edema (fluid buildup), changes in the rhythm or speed of the heartbeat, a type of heart rhythm disorder, heart attack, heart failure
- Raynaud's phenomenon, cold hands and feet
- Constriction of the pulmonary airways (especially in patients with pre-existing disease), difficulty in breathing, cough
- Indigestion, abdominal pain, vomiting
- Hair loss, silver-white skin rash (psoriasiform rash) or worsening of psoriasis, skin rash
- Muscle pain not caused by exercise
- Sexual dysfunction, decreased sexual desire
- Muscle weakness / fatigue.
Other side effects reported with the use of eye drops containing phosphates:
Very rarely, patients with severe damage to the clear membrane at the front of the eye (cornea) have developed opaque patches on the cornea due to calcium build-up during treatment.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Keep this medicine out of the sight and reach of children.
Keep the bottle in the outer carton to protect it from light.
Only use one bottle at a time.
Do not use this medicine after the expiry date which is stated on the bottle label and carton after EXP. The expiry date refers to the last day of the month.
Even if you have not used all of the solution, you should throw away the bottle four weeks after you first open it. This will help prevent infections. In order not to forget, write the date of opening in the space provided on the box.
Do not throw any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Other Information
What COMBIGAN contains
- The active ingredients are brimonidine tartrate and timolol.
- One milliliter of solution contains 2 mg of brimonidine tartrate and timolol maleate corresponding to 5 mg of timolol.
- The other ingredients are: benzalkonium chloride (a preservative), monobasic sodium phosphate monohydrate, disodium phosphate heptahydrate and purified water.
Small amounts of hydrochloric acid or sodium hydroxide can be added to bring the solution to the right pH level (a measure of the solution's acidity or alkalinity).
Description of the appearance of COMBIGAN and contents of the pack
COMBIGAN is a clear solution of yellow to green eye drops in a plastic bottle with a screw cap. Each bottle is approximately half full and contains 5 ml of solution. Packs containing 1 or 3 bottles are available. Not all pack sizes may be marketed.
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
COMBIGAN 2 MG / ML + 5 MG / ML EYE DROPS, SOLUTION
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of solution contains:
2.0 mg of brimonidine tartrate, equivalent to 1.3 mg of brimonidine 5.0 mg of timolol, as 6.8 mg of timolol maleate
Contains benzalkonium chloride 0.05 mg / ml.
For the full list of excipients, see section 6.1.
03.0 PHARMACEUTICAL FORM
Eye drops, solution.
Clear solution of yellow to green color.
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Reduction of intraocular pressure (IOP) in patients with chronic open angle glaucoma or ocular hypertension who do not respond sufficiently to topical beta-blockers.
04.2 Posology and method of administration
To avoid contamination of the eye or eye drops, the tip of the dropper must not come into contact with any surface.
Recommended dosage in adults (including elderly patients)
The recommended dose is one drop of Combigan in the treated eye (s), twice daily, approximately every 12 hours. If more than one topical ophthalmic product is required, the drugs should be administered at an interval of at least 5 minutes from each other.
As with all eye drops, to reduce possible systemic absorption, it is recommended to compress the lacrimal sac at the medial canthus (occlusion of the tear dot) or to close the eyelids for two minutes. This should be done immediately after instillation of each drop of eye drops. This could lead to a reduction in systemic side effects and an increase in local activity.
Use in renal and hepatic insufficiency
Combigan has not been studied in patients with hepatic or renal insufficiency. It is therefore necessary to proceed with caution in the treatment of these patients.
Use in children and adolescents
Combigan is contraindicated in neonates and children (less than 2 years of age) (see section 4.3 Contraindications, section 4.4 Special warnings and precautions for use, section 4.8 Undesirable effects and section 4.9 Overdose).
The safety and efficacy of Combigan in children and adolescents (2 to 17 years of age) have not been demonstrated and, therefore, use in these subjects is not recommended (see also sections 4.4 and 4.8).
04.3 Contraindications
• Hypersensitivity to the active substances or to any of the excipients.
• Airway hyperreactivity diseases, including current or previous 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 pacemaker, overt heart failure, cardiogenic shock.
• Use in infants and children (less than 2 years of age) (see section 4.8).
• Patients being treated with monoamine oxidase (MAO) inhibitors.
• Patients taking antidepressants that affect noradrenergic transmission (eg tricyclic antidepressants and mianserin).
04.4 Special warnings and appropriate precautions for use
Children aged two years and over, especially those aged between 2 and 7 years and / or weighing ≤ 20Kg, should be treated with caution and carefully monitored due to the high incidence and severity of somnolence. "Efficacy of Combigan in children and adolescents (2 to 17 years of age) has not been demonstrated (see section 4.2 and section 4.8).
In clinical studies, some patients have reported ocular allergy reactions (allergic conjunctiva and allergic blepharitis) after treatment with Combigan.
Allergic conjunctivitis was found in 5.2% of patients. Generally the onset of the reaction occurred between the 3rd and 9th month resulting in an overall discontinuation rate of 3.1% of patients. Allergic blepharitis has not been commonly reported (allergic reactions should be discontinued using Combigan.
Delayed ocular hypersensitivity reactions have been reported following the intake of 0.2% brimonidine tartrate ophthalmic solution, with some of these reports associated with an increase in IOP.
Like other topically applied ophthalmic agents, Combigan may be absorbed systemically. No increase in systemic absorption of the individual active substances was observed. Due to the beta-adrenergic component, timolol, the same type of cardiovascular, pulmonary and other adverse reactions as those occurring with beta- systemic blockers. The incidence of systemic adverse reactions after administration of topical ophthalmic medicinal products is lower than that of reactions following systemic administration. To reduce systemic absorption, see section 4.2.
Cardiac pathologies :
Patients with cardiovascular disease (e.g. coronary artery disease, Prinzmetal's angina and heart failure) and on hypotensive therapy with beta-blockers should be critically evaluated and therapy with other active substances should be considered. Patients with cardiovascular disease should be monitored for signs of worsening of these conditions and adverse events.
Due to its negative effect on conduction time, beta-blockers should be administered with caution to patients with first degree heart block.
As with systemic beta-blockers, if treatment needs to be stopped in coronary artery patients, this should be done gradually to avoid rhythm disturbances, myocardial infarction or sudden death.
Vascular pathologies :
Patients with severe peripheral circulatory disturbance / disorders (i.e. advanced forms of Raynaud's phenomenon or Raynaud's syndrome) should be treated with caution.
Respiratory pathologies :
Respiratory reactions, including death from 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.
Hypoglycemia / diabetes :
Beta-blockers should be administered with caution in patients prone to spontaneous hypoglycaemia or in patients with unstable diabetes, as beta-blockers may mask the signs and symptoms of acute hypoglycaemia.
Hyperthyroidism :
Beta blockers can also mask the signs of hyperthyroidism.
Combigan should be used with caution in patients with metabolic acidosis and untreated pheochromocytoma.
Corneal pathologies:
Ophthalmic beta-blockers can induce dry eyes. Patients with corneal disease should be treated with caution.
Other beta-blocking agents:
The effect on intraocular pressure or known effects of systemic beta-blocker may be potentiated when timolol is administered to patients already being treated with a systemic beta-blocker. The response of these patients should be closely monitored. The use of two Topical beta-adrenergic blocking agents is not recommended (see section 4.5).
Anaphylactic reactions:
During treatment with beta-blockers, patients with a history of atopy or a severe anaphylactic reaction caused by allergens of various kinds, may be more responsive to repeated stimulation with these allergens and not respond to the dose of adrenaline usually used for the treatment of anaphylactic reactions.
Detachment of the choroid:
Detachment of the choroid has been reported with the administration of therapies that reduce the production of aqueous humor (e.g. timolol, acetazolamide) after filter surgery procedures.
Surgical anesthesia:
? -Blocking ophthalmic preparations may block the systemic effects of? -Agonists, for example adrenaline. The anesthetist should be informed if the patient is taking timolol.
Timolol treatment has been associated with pronounced hypotension in patients with severe renal insufficiency on dialysis.
The preservative in Combigan, benzalkonium chloride, can cause eye irritation. Contact lenses must be removed before instillation and can be re-applied after at least 15 minutes.
Benzalkonium chloride is known to dull soft contact lenses. Avoid contact with soft contact lenses.
Combigan has not been studied in patients with narrow-angle glaucoma.
Athletes should be aware that Combigan contains timolol which may lead to a positive result in doping controls.
04.5 Interactions with other medicinal products and other forms of interaction
No interaction studies have been performed with the fixed combination of brimonidine and timolol. Although no specific interaction studies have been conducted with Combigan, the potential for additive or potentiating effects should be borne in mind when administered in combination with CNS depressants (alcohol, barbiturates, opiates, sedatives or anesthetics).
Co-administration of ophthalmic solutions of beta-blockers and oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics or guanethidine may lead to additive effects, such as hypotension and / or marked bradycardia. In addition, very rare cases have been reported (systemic antihypertensives.
Occasionally, mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported.
Beta-blockers may potentiate the blood glucose lowering effect of antidiabetics and mask the signs and symptoms of hypoglycaemia (see section 4.4 Special warnings and precautions for use).
The hypertensive reaction caused by abrupt withdrawal of clonidine may be potentiated while taking beta-blockers.
Enhanced systemic beta receptor blockade (e.g. decreased heart rate, depression) has been reported during concomitant treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.
The use of a beta-blocker concomitantly with anesthetic drugs may attenuate compensatory tachycardia and increase the risk of hypotension (see section 4.4); therefore, the anesthetist should be informed if the patient is being treated with Combigan.
Caution is advised when treatment with Combigan together with iodine-based contrast media or with intravenous lidocaine.
Cimetidine, hydralazine and alcohol can increase plasma concentrations of timolol.
No data are available on the level of catecholamines in circulation after administration of Combigan. However, caution is recommended in patients taking drugs that can alter the metabolism and uptake of circulating amines (eg chlorpromazine, methylphenidate, reserpine).
It is also recommended to exercise caution in case of initiation (or dose variation) of concomitant treatment with systemic drugs (regardless of pharmaceutical form) which may interact with alpha-adrenergic agonists or interfere with their activity, i.e. agonists or adrenergic receptor antagonists (e.g. isoprenaline, prazosin).
Although specific drug interaction studies of Combigan have not been conducted, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered.
Administration of brimonidine is contraindicated in patients already on monoamine oxidase (MAO) inhibitor therapy and in patients on antidepressant therapy that have an effect on noradrenergic transmission (e.g. tricyclic antidepressants and mianserin) (see section 4.3).
Patients who have been on MAO inhibitor therapy should wait 14 days after stopping before starting treatment with Combigan.
04.6 Pregnancy and breastfeeding
Pregnancy
There are no adequate data on the use of brimonidine / timolol fixed combination in pregnant women.
Combigan should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see section 4.2.
Brimonidine tartrate
There are no adequate data on the use of brimonidine tartrate in pregnant women. Animal studies have shown reproductive toxicity at high doses already toxic to the mother (see section 5.3 Preclinical safety data). The potential risk is unknown. man.
Timolol
Studies in animals have shown reproductive toxicity at significantly higher doses than those used in clinical practice (see section 5.3). Epidemiological studies have not revealed malformative effects but have shown a risk of intrauterine growth retardation during administration of oral beta-blockers. In addition, signs and symptoms of beta blockade (e.g. bradycardia, hypotension, respiratory distress, and hypoglycaemia) were observed in the newborn when beta-blockers were administered to the mother until delivery. If Combigan is administered during pregnancy up to the time of delivery, the neonate should be closely monitored during the first days of life.
Feeding time
Brimonidine tartrate
It is not known whether brimonidine is excreted in human milk but is excreted in the milk of rats.
Timolol
Beta-blockers are excreted in human milk. However, at therapeutic doses of timolol in eye drops, it is unlikely that sufficient quantities are present in breast milk to produce clinical symptoms of beta-blockade in the neonate. To reduce systemic absorption, see section 4.2.
Combigan should therefore not be used by women who are breastfeeding.
04.7 Effects on ability to drive and use machines
Combigan has little influence on the ability to drive and use machines.
Combigan may cause temporary blurring of vision, visual disturbances, fatigue and / or sleepiness which may affect the ability to drive or use machines. The patient should wait until these symptoms have passed before driving or using machines.
04.8 Undesirable effects
Based on 12-month clinical data, the most frequently reported adverse drug reactions (ADRs) were conjunctival hyperaemia (in approximately 15% of patients) and burning sensation in the eye (in approximately 11% of patients). In most of these cases the effects were mild, with discontinuation rates limited to 3.4% and 0.5%, respectively.
The following adverse drug reactions were reported during clinical trials with Combigan:
Eye disorders
Very common (> 1/10): conjunctival hyperemia, burning.
Common (> 1/100, allergic conjunctivitis, corneal erosion, superficial punctate keratitis, ocular pruritus, conjunctival folliculosis, visual disturbance, blepharitis, epiphora, dry eye, ocular discharge, eye pain, eye irritation, foreign body sensation.
Uncommon (> 1/1000, conjunctival edema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, fly flies, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival pallor, corneal edema, corneal infiltrates, vitreous detachment.
Psychiatric disorders
Common (> 1/100,
Nervous system disorders
Common (> 1/100, headache.
Uncommon (> 1/1000, dizziness, syncope.
Cardiac pathologies
Uncommon (> 1/1000, palpitations.
Vascular pathologies
Common (> 1/100,
Respiratory, thoracic and mediastinal disorders
Uncommon (> 1/1000, rhinitis, nasal dryness.
Gastrointestinal disorders
Common (> 1/100, dry mouth.
Uncommon (> 1/1000, taste disturbance, nausea, diarrhea.
Skin and subcutaneous tissue disorders
Common (> 1/100, eyelid erythema.
Uncommon (> 1/1000, allergic contact dermatitis.
General disorders and administration site conditions
Common (> 1/100, asthenia.
Since the marketing of Combigan, the following adverse reactions have been reported:
Eye disorders
Not known: blurred vision
Cardiac pathologies
Not known: arrhythmia, bradycardia, tachycardia
Vascular pathologies
Not known: hypotension
Skin disorders
Not known: facial erythema
Other adverse events have been observed with one of the components and can therefore also occur with Combigan:
Brimonidine
Eye disorders: iritis, iridocyclitis (anterior uveitis), miosis
Psychiatric disorders: insomnia
Respiratory, thoracic and mediastinal disorders: upper respiratory tract symptoms, dyspnoea
Gastrointestinal disorders: gastrointestinal symptoms
General disorders and administration site conditions: systemic allergic reactions
Skin and subcutaneous tissue disorders: skin reactions including erythema, face edema, pruritus, rash and vasodilation
In cases where brimonidine has been used as part of the medical treatment of congenital glaucoma, symptoms of brimonidine overdose, such as loss of health, have been reported in infants and children (less than 2 years of age) treated with brimonidine. consciousness, lethargy, somnolence, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, pallor, respiratory depression and apnea (see section 4.3).
In children aged two years and over, especially those aged 2 to 7 years and / or with weight
Timolol
Like other topically applied ophthalmic medicinal products, Combigan (brimonidine tartrate / timolol) is absorbed into the systemic circulation. Absorption of timolol may cause undesirable effects similar to those seen with systemic beta-blockers.
The incidence of systemic adverse reactions after administration of topical ophthalmic medicinal products is lower than that of reactions following systemic administration. To reduce systemic absorption, see section 4.2.
Other adverse reactions observed with ophthalmic beta-blockers and which may possibly also occur with Combigan are listed below:
Immune system disorders: systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reactions
Metabolism and nutrition disorders: hypoglycemia
Psychiatric disorders: insomnia, nightmares, memory loss
Nervous system disorders: cerebrovascular accident, cerebral ischaemia, worsening of the signs and symptoms of myasthenia gravis, paraesthesia
Eye disorders: keratitis, choroid detachment following filter surgery, (see section 4.4 Special warnings and precautions for use), reduced corneal sensitivity, corneal erosion, ptosis, diplopia
Cardiac disorders: chest pain, edema, atrioventricular block, cardiac arrest, heart failure
Vascular disorders: Raynaud's phenomenon, feeling of cold in the extremities
Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic 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
04.9 Overdose
Rare reports of overdose with Combigan in humans have shown no adverse outcome. Treatment of overdose includes symptomatic supportive therapy; the patient's airways must be kept clear.
Brimonidine
Ophthalmic Overdose (Adults) :
In cases received, the events reported were generally those already referred to as adverse reactions.
Systemic overdose caused by accidental ingestion (Adults) :
There is very limited information on accidental ingestion of brimonidine in adults. The only adverse event reported to date has been hypotension. It has been reported that the hypotensive episode was followed by a hypertensive rebound. Oral overdose with other alpha-2 agonists resulted in symptoms such as hypotension, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmia, miosis, apnea, hypotonia, hypothermia, respiratory depression and convulsions.
Pediatric population :
Several reports of serious adverse events following inadvertent ingestion of brimonidine by pediatric subjects have been published or reported to Allergan. Subjects had symptoms of central nervous system depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression, and apnea, and required, when indicated, admission to intensive care with intubation. Full recovery was reported for all subjects within 6-24 hours.
Timolol
Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study in some patients showed that timolol is not rapidly dialyzed.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals - Antiglaucoma and miotic preparations - beta-blocking agents - timolol, combinations
ATC code: S01 ED51
Mechanism of action
Combigan is composed of two active ingredients: brimonidine tartrate and timolol maleate. These two components reduce elevated intraocular pressure (IOP) thanks to complementary mechanisms of action and the combined effect leads to a greater IOP reduction than the components administered individually. Combigan acts quickly.
Brimonidine tartrate is an alpha-2-adrenergic receptor agonist, 1000 times more selective towards alpha-2 adrenoceptors than alpha-1 adrenoceptors. This receptor selectivity means that the active principle does not cause mydriasis, nor vasoconstriction at the level of the microvessels in the human retinal xenograft.
Brimonidine tartrate is believed to reduce IOP by increasing uveoscleral outflow and reducing the production of aqueous humor.
Timolol non-selectively blocks beta-1 and beta-2 adrenergic receptors, lacking significant intrinsic sympathomimetic activity, as well as direct myocardial sedative effect or local anesthetic (membrane stabilizing) action. Timolol lowers IOP by decreasing the production of aqueous humor. The exact mechanism of action has not been clearly established but inhibition of cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is likely.
Clinical Effects
In three double-blind, controlled clinical trials, Combigan (twice daily) resulted in a clinically significant additive decrease in mean diurnal IOP compared to timolol (twice daily) and brimonidine (two or three times daily) administered. in monotherapy.
In a study in patients whose IOP was insufficiently controlled, after a minimum three-week run-in period with any monotherapy, treatment for three months with Combigan (twice daily), timolol (twice daily) and brimonidine (twice daily) showed further reductions in mean diurnal IOP of 4.5, 3.3 and 3.5 mmHg, respectively. In this study, prior to administration, a significant additional decrease in IOP can be demonstrated only in comparison with brimonidine but not with timolol, although a positive trend and superiority is noted in all other pre-determined control analyzes over time.
By collecting and analyzing data from the other two clinical studies together, statistical superiority over timolol is found in all measurements.
Furthermore, the magnitude of the reduction in IOP obtained with Combigan was consistently no less than that obtained with the combination therapy brimonidine and timolol (both twice daily).
Double-blind studies have shown that the lowering of the IOP obtained with Combigan is maintained for up to 12 months.
05.2 Pharmacokinetic properties
Combigan
Plasma concentrations of brimonidine and timolol were determined in a crossover study and by comparing treatments with monotherapies and Combigan in healthy volunteers. There were no statistically significant differences in the AUCs of brimonidine or timolol when comparing Combigan and their respective monotherapy treatments.
After administration of Combigan, the mean plasma C values of brimonidine and timolol were 0.0327 and 0.406 ng / ml, respectively.
Brimonidine
Plasma concentrations of brimonidine in humans are low following ocular administration of 0.2% eye drops. Brimonidine is not significantly metabolised in the human eye and plasma protein binding is approximately 29%. Afterwards. topical administration in humans, the mean apparent half-life in the systemic circulation was approximately 3 hours.
Following oral administration in humans, brimonidine is well absorbed and rapidly eliminated. Most of the dose (approximately 74%) is excreted in the urine as metabolites over a period of five days; there is no unmodified drug in the urine. In vitro studies, conducted on animal and human liver, indicate that metabolism is largely mediated by aldehyde oxidase and cytochrome P450, so that systemic elimination appears to be mainly entrusted to hepatic metabolism.
In ocular tissues, brimonidine binds significantly and reversibly to melanin without this causing undesirable effects. In the absence of melanin there is no accumulation.
The metabolism of brimonidine in the human eye is not relevant.
Timolol
The maximum concentration in the aqueous humor, in man, of 0.5% eye drops in subjects to undergo cataract surgery, was equal to 898 ng / ml approximately 1 hour after administration. Part of the dose is absorbed systemically and then metabolised primarily in the liver. The plasma half-life of timolol is approximately 7 hours. Timolol is partly metabolised by the liver and excreted, as unmodified timolol and as metabolites, by the kidney. Timolol does not bind significantly to plasma proteins.
05.3 Preclinical safety data
The ocular and systemic safety of the individual components is well established. Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. the man.
Brimonidine
Brimonidine tartrate did not show teratogenic effects in animals, but caused abortions in rabbits and reduced postnatal growth in rats at systemic exposure levels approximately 37 and 134 times respectively those experienced in humans during treatment.
Timolol
In animal studies, beta-blockers have been shown to produce decreased umbilical blood flow, decreased fetal growth, delayed bone formation and increased fetal and postnatal death, but not teratogenic. Embryonic toxicity (resorption) in rabbits and fetal toxicity (delayed ossification) in rats were found with high dose timolol administered to the mother. Teratogenicity studies conducted in mice, rats and rabbits at oral doses of timolol up to 4200 times the daily human dose of Combigan showed no signs of fetal malformation.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Benzalkonium chloride
Monobasic sodium phosphate monohydrate
Disodium phosphate heptahydrate
Hydrochloric acid or sodium hydroxide to correct the pH
Purified water
06.2 Incompatibility
Not relevant.
06.3 Period of validity
21 months
After first opening: use within 28 days
06.4 Special precautions for storage
Keep the bottle in the outer carton to protect it from light.
06.5 Nature of the immediate packaging and contents of the package
White low density polyethylene bottles with polystyrene screw caps.
Each bottle has a fill volume of 5ml.
The following packs are available: box containing 1 or 3 bottles of 5 ml. Not all pack sizes may be marketed.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Allergan Pharmaceuticals Ireland
Castlebar Road
Westport
Co. Mayo
Ireland
08.0 MARKETING AUTHORIZATION NUMBER
037083019 / M 0.2% + 0.5% eye drops solution, bottle of 5 ml
037083021 / M 0.2% + 0.5% eye drops solution 3 bottles of 5 ml
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Date of first authorization: 5 December
2006 Date of last renewal: 30 March 2010
10.0 DATE OF REVISION OF THE TEXT
02/2012
