Summary of medicine characteristics - ECBIRIO 0.3 MG / ML + 5 MG / ML EYE DROPS SOLUTION
Ecbirio 0.3 mg/ml + 5 mg/ml eye drops, solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml of solution contains 0.3 mg of bimatoprost and 5 mg of timolol (as 6.8 mg of timolol maleate).
Each bottle contains 3 ml solution.
Excipient with known effect: phosphates.
Each ml of solution contains 1.4 mg phosphates.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Eye drops, solution
Transparent, colourless solution
pH: 6.8 to 7.6
Osmolality: 270 to 320 mOsmol/kg
4.1 Therapeutic indications
Reduction of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers or prostaglandin analogues.
4.2 Posology and method of administration
Posology
Recommended dosage in adults (including older people)
The recommended dose is one drop of Ecbirio in the affected eye(s) once daily, administered either in the morning or in the evening. It should be administered at the same time each day.
Existing literature data for bimatoprost/timolol (multi-dose formulation) suggest that evening dosing may be more effective in IOP lowering than morning dosing.
However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing (see section 5.1).
If one dose is missed, treatment should continue with the next dose as planned. The dose should not exceed one drop in the affected eye(s) daily.
Renal and hepatic impairment
Bimatoprost/timolol has not been studied in patients with hepatic or renal impairment. Therefore caution should be used in treating such patients.
Paediatric population
The safety and efficacy of Ecbirio in children aged less than 18 years has not been established. No data are available.
Method of administration
For ocular use only.
Ecbirio is a sterile solution that does not contain a preservative.
Before instillation of the eye drops:
– When using for the first time, before delivering a drop to the eye, a patient should first of all practice using the dropper bottle by squeezing it slowly to deliver one drop into the air, away from the eye.
– When a patient is confident that he can deliver one drop at a time, he should choose the position that he finds most comfortable for the instillation of the drops (patient can sit down, lie on his back, or stand in front of a mirror).
Instructions for use:
1. A patient should wash his hands carefully before using this medicine.
2. If the packaging or bottle is damaged the medicine should not be used.
3. When using the medicine for the first time, the cap should unscrewed aafter making sure that the sealed ring on the cap has not been broken. A patient should feel a slight resistance until this tamper-proof ring breaks off
4. If the tamper-proof ring is loose it should be thrown away because it may fall into the eye and cause injuries.
5. A patient should tilt his head back and gently pull down his lower eyelid to form a pouch between his eye and eyelid. (Contact between the tip of the bottle and eye, eyelids or fingers should be avoided).
6. One drop should be instilled into the pouch by pressing slowly on the bottle. A patient should squeeze the bottle gently in the middle and let a drop fall into his eye. There might be a few seconds delay between squeezing and the drop coming out. A patient should not squeeze too hard if he is not sure how to administer this medicine, he should ask doctor, pharmacist or nurse.
7. Then the patient should compress the tear duct for about 2 minutes (by pressing a finger against the corner of the eye by the nose) and close his eye(s) and keep it/them closed during this time. This ensures that the drop is absorbed by the eye and that the amount of medicine draining through the tear duct to the nose will probably be reduced.
8. The patient should repeat steps 5 and 6 in his other eye if the doctor has told him to do this.
9. After use and prior to recapping, the bottle should be shaken once in a downwards direction, without touching the dropper tip, in order to remove any residual liquid on the tip. This is necessary in order to ensure delivery of subsequent drops. After instillation the cap on the bottle should be screwed.
When using nasolacrimal occlusion or closing the eyelids for 2 minutes, the systemic absorption is reduced. This may result in a decrease in systemic side effects and an increase in local activity.
If more than one topical ophthalmic medicinal product is being used, each one should be administered at least 5 minutes apart. Eye ointments should be administered last.
4.3 Contraindications
Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.
Reactive airway disease including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block, not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.
4.4 Special warnings and precautions for use
Like other topically applied ophthalmic medicinal products, the active substances bimatoprost/timolol may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed with bimatoprost/timolol (multi-dose formulation). Due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions (ADRs) as seen with systemic beta-blockers 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
Patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and receiving hypotension therapy with beta-blockers should be critically assessed and 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 the negative effect on conduction time, beta-blockers 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.
Ecbirio 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.
Endocrine disorders
Beta-adrenergic blocking medicinal products should be administered with caution in patients subject to spontaneous hypoglycaemia or in patients with labile diabetes as beta-blockers may mask the signs and symptoms of acute hypoglycemia.
Beta-blockers may also mask the signs of hyperthyroidism.
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 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 allergens 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 anaesthesiologist should be informed when the patient is receiving timolol.
Hepatic
In patients with a history of mild liver disease or abnormal alanine aminotransferase (ALT), aspartate aminotransferase (AST) and/or bilirubin at baseline, bimatoprost eye drops had no adverse reactions on liver function over 24 months. There are no known adverse reactions of ocular timolol on liver function.
Ocular
Before treatment is initiated, patients should be informed of the possibility of eyelash growth, and periorbital skin hyperpigmentation since these have been observed during treatment with bimatoprost/timolol. Increased brown iris pigmentation has also been observed during treatment with bimatoprost/timolol (multi-dose formulation). Increased iris pigmentation is likely to be permanent, and may lead to differences in appearance between the eyes if only one eye is treated. After discontinuation of bimatoprost/timolol, pigmentation of iris may be permanent. After 12 months of treatment with bimatoprost/timolol (multi-dose formulation), the incidence of iris pigmentation was 0.2%. After 12 months of treatment with bimatoprost eye drops alone, the incidence was 1.5% and did not increase following 3 years of treatment. The pigmentation change is due to increased melanin content in the melanocytes rather than to an increase in the number of melanocytes. The long term effects of increased iridial pigmentation are not known. Iris color changes seen with ophthalmic administration of bimatoprost may not be noticeable for several months to years. Neither nevi nor freckles of the iris appear to be affected by treatment. Periorbital tissue pigmentation has been reported to be reversible in some patients.
Macular oedema, including cystoid macular oedema has been reported with bimatoprost/timolol (multi-dose formulation). Therefore, Ecbirio should be used with caution in aphakic patients, in pseudophakic patients with a torn posterior lens capsule, or in patients with known risk factors for macular oedema (e.g. intraocular surgery, retinal vein occlusions, ocular inflammatory disease and diabetic retinopathy).
Ecbirio should be used with caution in patients with active intraocular inflammation (e.g. uveitis) because the inflammation may be exacerbated.
Skin
There is a potential for hair growth to occur in areas where Ecbirio solution comes repeatedly in contact with the skin surface. Thus, it is important to apply Ecbirio as instructed and avoid it running onto the cheek or other skin areas.
Other conditions
Bimatoprost/timolol has not been studied in patients with inflammatory ocular conditions, neovascular, inflammatory, angle-closure, congenital or narrow-angle glaucoma.
In studies of bimatoprost 0.3 mg/ml in patients with glaucoma or ocular hypertension, it has been shown that more frequent exposure of the eye to more than 1 dose of bimatoprost daily may decrease the IOP-lowering effect. Patients using Ecbirio with other prostaglandin analogs should be monitored for changes to their intraocular pressure.
Patients with a history of contact hypersensitivity to silver should not use this product as dispensed drops may contain traces of silver.
4.5 Interaction with other medicinal products and other forms of interaction
No specific interaction studies have been performed with the bimatoprost/timolol fixed combination.
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, guanethidine, beta-adrenergic blocking agents, parasympathomimetics, anti-arrhythmics (including amiodarone) and digitalis glycosides.
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.
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data from the use of the bimatoprost/timolol fixed combination in pregnant women. Ecbirio should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.
Bimatoprost
No adequate clinical data in exposed pregnancies are available. Animal studies have shown reproductive toxicity at high maternotoxic doses (see section 5.3).
Timolol
Epidemiological studies have not revealed malformative effects but 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 bimatoprost/timolol is administered until delivery, the neonate should be carefully monitored during the first days of life. Animal studies with timolol have shown reproductive toxicity at doses significantly higher than would be used in clinical practice (see section 5.3).
Breastfeeding
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.
Bimatoprost
It is not known if bimatoprost is excreted in human breast milk but it is excreted in the milk of the lactating rat. Ecbirio should not be used by breast-feeding women.
Fertility
There are no data on the effects of Ecbirio on human fertility.
4.7 Effects on ability to drive and use machines
Ecbirio has negligible influence on the ability to drive and use machines. As with any topical ocular treatment, if transient blurred vision occurs at instillation, the patient should wait until the vision clears before driving or using machines.
4.8 Undesirable effects
Bimatoprost/timolol
Summary of the safety profile
The adverse reactions reported in the clinical study using bimatoprost/timolol singledose (preservative free) were limited to those earlier reported for either bimatoprost/timolol (multi-dose formulation, with preservative) or for the single active substances bimatoprost or timolol. No new adverse reactions specific for bimatoprost/timolol single-dose (preservative free) have been observed in clinical studies.
The majority of adverse reactions reported with bimatoprost/timolol single-dose (preservative free) were ocular, mild in severity and none were serious. Based on a 12-week study of bimatoprost/timolol single-dose (preservative free) administered once daily, the most commonly reported adverse reaction with bimatoprost/timolol in single-dose (preservative free) was conjunctival hyperaemia (mostly trace to mild and thought to be of a non-inflammatory nature) in approximately 21% of patients and led to discontinuation in 1.4% of patients.
Tabulated list of adverse reactions
Table 1 presents the adverse reactions that were reported during clinical studies of both bimatoprost/timolol single-dose (preservative free) and bimatoprost/timolol multi-dose (with preservative) formulations (within each frequency grouping, adverse reactions are presented in order of decreasing seriousness) or in the post-marketing period.
The frequency of possible adverse reactions listed below is defined using the following convention:
| 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 | Frequency cannot be estimated from available data |
Tabel 1
| System Organ Class | Frequency | Adverse reaction |
| Immune system disorders | Not known | hypersensitivity reactions including signs or symptoms of allergic dermatitis, angioedema, eye allergy |
| Psychiatric disorders | Not known | insomnia2, nightmare2 |
| Nervous system disorders | Common | headache, |
| Not known | dizziness2 ,dysgeusia2 | |
| Eye disorders | Very common | conjunctival hyperaemia |
| Common | punctuate keratitis, corneal erosion2, burning sensation2, conjunctival irritation1, eye pruritus, stinging sensation in the eye2, foreign body sensation, dry eye, erythema of eyelid, eye pain, photophobia, eye discharge2, visual disturbance2, eyelid pruritus, visual acuity worsened2, blepharitis2, eyelid oedema, eye irritation, lacrimation increased, growth of eyelashes | |
| Uncommon | iritis2, conjunctival oedema2, eyelid pain2, abnormal sensation in the eye1, asthenopia, trichiasis2, iris hyperpigmentation2, deepening of eyelid sulcus, eyelid retraction2, eyelash discolouration (darkening)1 | |
| Not known | cystoid macular oedema2, eye |
| swelling, vision blurred2 | ||
| Cardiac disorders | Not known | bradycardia |
| Respiratory, thoracic and mediastinal disorders | Common | rhinitis2 |
| Uncommon | dyspnoea | |
| Not known | bronchospasm (predominantly in patients with pre-existing bronchospastic disease)2, asthma | |
| Skin and subcutaneous tissue disorders | Common | blepharal pigmentation2, hirsutism2, skin hyperpigmentation (periocular) |
| Not known | alopecia2 | |
| General disorders and administration site conditions | Not known | fatigue |
1adverse reactions only observed with bimatoprost/timolol preservative-free formulation
2adverse reactions only observed with bimatoprost/timolol formulation with preservative (benzalkonium chloride)
Like other topically applied ophthalmic drugs, bimatoprost/timolol is absorbed into the systemic circulation. Absorption of timolol may cause similar undesirable effects as seen with systemic beta-blocking agents. The 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 either of the active substances (bimatoprost or timolol), and may potentially occur also with bimatoprost/timolol are listed below in Table 2:
Table 2
| System Organ Class | Adverse reaction |
| Immune system disorders | systemic allergic reactions including anaphylaxis1 |
| Metabolism and nutrition disorders | hypoglycaemia1 |
| Psychiatric disorders | depression1, memory loss1, hallucination1 |
| Nervous system disorders | syncope1, cerebrovascular accident1, increase in signs and symptoms of myasthenia gravis1, paraesthesia1, cerebral ischaemia1, dizziness2 |
| Eye disorders | decreased corneal sensitivity1, diplopia1, ptosis1, choroidal detachment following filtration surgery (see section 4.4)1, keratitis1, blepharospasm2, retinal haemorrhage2, uveitis2, eye discharge2, 2 2 2 ocular discomfort |
| Cardiac disorder | atrioventricular block1, cardiac arrest1, arrhythmia1, cardiac failure1, congestive heart failure1, chest pain1, palpitations1, oedema1 |
| Vascular disorders | hypotension1, , Raynaud’s phenomenon1, cold hands and feet1 |
| Respiratory, thoracic and mediastinal disorders | asthma exacerbation2, COPD exacerbation2, cough1 |
| Gastrointestinal disorders | nausea1,2, diarrhoea1, dyspepsia1, dry mouth1, abdominal pain1, vomiting1 |
| Skin and subcutaneous tissue disorders | psoriasiform rash1 or exacerbation of psoriasis1, skin rash1, skin discoloration (periocular)2 |
| Musculoskeletal and connective tissue disorders | myalgia1 |
| Reproductive system and breast disorders | sexual dysfunction1, decreased libido1 |
| General disorders and administration site conditions | asthenia1,2 |
| Investigations | liver function tests (LFT) abnormal2 |
1 adverse reactions observed with timolol
2 adverse reactions observed with bimatoprost
Adverse reactions reported in phosphate containing eye drops
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 of suspected adverse reactions
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 the Yellow Card Scheme at www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
4.9 Overdose
4.9 OverdoseA topical overdose with bimatoprost/timolol is not likely to occur or to be associated with toxicity.
Bimatoprost
If bimatoprost/timolol is accidentally ingested, the following information may be useful: in two-week oral mice and rats studies, doses of bimatoprost up to 100 mg/kg/day did not produce any toxicity. This dose expressed as mg/m2 is at least 70-times higher than the accidental dose of one bottle of bimatoprost/timolol in a 10 kg child.
Timolol
Symptoms of systemic timolol overdose include: bradycardia, hypotension, bronchospasm, headache, dizziness, shortness of breath, and cardiac arrest. A study of patients with renal failure showed that timolol did not dialyse readily.
If overdose occurs treatment should be symptomatic and supportive.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: ophthalmological, beta-blocking agents, ATC code: S01ED51
Mechanism of action
Ecbirio consists of two active substances: bimatoprost and timolol. These two components decrease elevated intraocular pressure (IOP) by complementary mechanisms of action and the combined effect results in additional IOP reduction compared to either compound administered alone. Ecbirio has a rapid onset of action.
Bimatoprost is a potent ocular hypotensive active substance. It is a synthetic prostamide, structurally related to prostaglandin F2a (PGF2a) that does not act through any known prostaglandin receptors. Bimatoprost selectively mimics the effects of newly discovered biosynthesised substances called prostamides. The prostamide receptor, however, has not yet been structurally identified. The mechanism of action by which bimatoprost reduces intraocular pressure in man is by increasing aqueous humour outflow through the trabecular meshwork and enhancing uveoscleral outflow.
Timolol is a beta1 and beta2 non-selective adrenergic receptor blocking agent that does not have significant intrinsic sympathomimetic, direct myocardial depressant, or local anaesthetic (membrane-stabilising) activity. Timolol lowers IOP by reducing aqueous humour formation. The precise mechanism of action is not clearly established, but inhibition of the increased cyclic AMP synthesis caused by endogenous beta-adrenergic stimulation is probable.
Clinical effects
A 12-week (double-masked, randomized, parallel group) clinical study compared the efficacy and safety of bimatoprost/timolol in single-dose (preservative free) with bimatoprost/timolol (multi-dose formulation, with preservative) in patients with glaucoma or ocular hypertension. Bimatoprost/timolol single dose (preservative free) achieved noninferior IOP-lowering efficacy to bimatoprost/timolol (multi-dose formulation, with preservative): the upper limit of the 95% CI of the between-treatment difference was within the pre-defined 1.5 mm Hg margin at each timepoint evaluated (hours 0, 2, and 8) at week 12 (for the primary analysis), and also at weeks 2 and 6, for mean worse eye IOP change from baseline (worse eye IOP refers to the eye with the higher mean diurnal IOP at baseline). In fact, the upper limit of the 95% CI did not exceed 0.14 mm Hg at week 12.
Both treatment groups showed statistically and clinically significant mean decreases from baseline in worse eye IOP at all follow up timepoints throughout the study (p < 0.001). Mean changes from baseline worse eye IOP ranged from –9.16 to –7.98 mm Hg for bimatoprost/timolol (single-dose, preservative free) group, and from –9.03 to –7.72 mm Hg for the bimatoprost/timolol (multi-dose formulation, with preservative) group across the 12-week study.
Bimatoprost/timolol in single-dose (preservative free) also achieved equivalent IOP-lowering efficacy to bimatoprost/timolol (multi-dose formulation, with preservative) in average eye and worse eye IOP at each follow-up timepoint at weeks 2, 6 and 12.
Based on studies of bimatoprost/timolol (multi-dose formulation, with preservative), the IOP-lowering effect of bimatoprost/timolol is non-inferior to that achieved by adjunctive therapy of bimatoprost (once daily) and timolol (twice daily).
Existing literature data for bimatoprost/timolol (multi-dose formulation, with preservative) suggest that evening dosing may be more effective in IOP lowering than morning dosing. However, consideration should be given to the likelihood of compliance when considering either morning or evening dosing.
Paediatric population
The safety and efficacy of bimatoprost/timolol in children aged less than 18 years has not been established.
5.2 Pharmacokinetic properties
Bimatoprost/timolol medicinal product
Plasma bimatoprost and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to bimatoprost/timolol (multi-dose formulation) treatment in healthy subjects. Systemic absorption of the individual components was minimal and not affected by co-administration in a single formulation.
In two 12-month studies of bimatoprost/timolol (multi-dose formulation) in which systemic absorption was measured, no accumulation was observed of either of the individual components.
Bimatoprost
Bimatoprost penetrates the human cornea and sclera well in vitro. After ocular administration, the systemic exposure of bimatoprost is very low with no accumulation over time. After once daily ocular administration of one drop of 0.03% bimatoprost to both eyes for two weeks, blood concentrations peaked within 10 minutes after dosing and declined to below the lower limit of detection (0.025 ng/ml) within 1.5 hours after dosing. Mean Cmax and AUC 0–24hrs values were similar on days 7 and 14 at approximately 0.08 ng/ml and 0.09 ng^hr/ml respectively, indicating that a steady drug concentration was reached during the first week of ocular dosing.
Bimatoprost is moderately distributed into body tissues and the systemic volume of distribution in humans at steady-state was 0.67 1/kg. In human blood, bimatoprost resides mainly in the plasma. The plasma protein binding of bimatoprost is approximately 88%.
Bimatoprost is the major circulating species in the blood once it reaches the systemic circulation following ocular dosing. Bimatoprost then undergoes oxidation, N-deethylation and glucuronidation to form a diverse variety of metabolites.
Bimatoprost is eliminated primarily by renal excretion, up to 67% of an intravenous dose administered to healthy volunteers was excreted in the urine, 25% of the dose was excreted via the faeces. The elimination half-life, determined after intravenous administration, was approximately 45 minutes; the total blood clearance was 1.5 1/hr/kg.
Characteristics in older people
After twice daily dosing of bimatoprost 0.3 mg/ml, the mean AUC 0–24hrs value of 0.0634 ng^hr/ml bimatoprost in the elderly (subjects 65 years or older) were significantly higher than 0.0218 ng^hr/ml in young healthy adults. However, this finding is not clinically relevant as systemic exposure for both elderly and young subjects remained very low from ocular dosing. There was no accumulation of bimatoprost in the blood over time and the safety profile was similar in elderly and young patients.
Timolol
After ocular administration of a 0.5% eye drops solution in humans undergoing cataract surgery, peak timolol concentration was 898 ng/ml in the aqueous humour at one hour post-dose. Part of the dose is absorbed systemically where it is extensively metabolised in the liver. The half-life of timolol in plasma is about 4 to 6 hours.
Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma.
5.3 Preclinical safety data
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Disodium phosphate dodecahydrate
Citric acid monohydrate
Sodium chloride
Sodium hydroxide or hydrochloric acid, diluted (for pH-adjustment)
Water for injection
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 years
Discard 90 days after the first opening of the bottle.
6.4 Special precautions for storage
This medicinal product does not require any special storage conditions.
Chemical and physical in-use stability has been demonstrated for 90 days at 25±2°C.
From a microbiological point of view, once opened, the product may be stored for a maximum of 90 days below 25°C. Other in-use storage times and conditions are the responsibility of the user.
6.5 Nature and contents of container
White 5 ml LDPE bottle containing 3 ml of solution with a multidose HDPE dropper applicator and a tamper-proof HDPE screw cap.
The dropper applicator has a silicon valve system that prevents backflow of contaminated liquid into the bottle and allows an inflow of filtered air.
Pack sizes:
Cartons containing 1 or 3 bottles each containing 3 ml of solution.
Not all pack sizes may be marketed.