Brimonidine Tartrate/Timolol 2 Mg/Ml + 5 Mg/Ml Eye Drops Solution
SUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Brimonidine Tartrate/Timolol 2 mg/ml + 5 mg/ml Eye Drops, Solution
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
One ml solution contains:
- 2.0 mg brimonidine tartrate, equivalent to 1.3 mg of brimonidine,
- 5.0 mg timolol as 6.8 mg timolol maleate.
Excipient with known effect
Contains benzalkonium chloride 0.05 mg/ml.
For the full list of excipients, see section 6.1.
3 PHARMACEUTICAL FORM
Eye drops, solution.
Clear, greenish-yellow solution. Osmolality 260 - 320 mOsmol/kg pH 6.6 - 7.2
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Reduction of intraocular pressure (IOP) in patients with chronic open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers.
4.2 Posology and method of administration
To avoid contamination of the eye or eye drops do not allow the dropper tip to come into contact with any surface.
Posology in adults (including older people)
The recommended dose is one drop of brimonidine tartrate/timolol in the affected eye(s) twice daily, approximately 12 hours apart. If more than one topical ophthalmic product is to be used, the different products should be instilled at least 5 minutes apart.
Method of administration
As with any eye drops, 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: it is recommended that the lachrymal sac be compressed at the medial canthus (punctual occlusion) for two minutes. This should be performed immediately following the instillation of each drop.
Special populations
Use in renal and hepatic impairment
Brimonidine tartrate/timolol has not been studied in patients with hepatic or renal impairment. Therefore, caution should be used in treating such patients.
Paediatric population
Brimonidine tartrate/timolol is contraindicated in neonates and infants (less than 2 years of age) (see sections 4.3, 4.4,4.8 and 4.9).
The safety and effectiveness of brimonidine tartrate/timolol 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 sections 4.4 and 4.8)
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 a pace-maker, overt cardiac failure, cardiogenic shock.
- Use in neonates and infants (less than 2 years of age) (see section 4.8)
- Patients receiving monoamine oxidase (MAO) inhibitor therapy.
- Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin)
4.4 Special warnings and precautions for use
Children of 2 years of age and above, especially those in the 2-7 age range and/or weighing <20 kg, should be treated with caution and closely monitored due to the high incidence of somnolence. The safety and effectiveness of brimonidine tartrate/timolol in children and adolescents (2 to 17 years of age) have not been established (see sections 4.2 and 4.8).
Like other topically applied ophthalmic agents, brimonidine tartrate/timolol may be absorbed systemically. No enhancement of the systemic absorption of the individual active substances has been observed. However, due to the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.
Some patients have experienced ocular allergic type reactions (allergic conjunctivitis and allergic blepharitis) with brimonidine tartrate/timolol 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 brimonidine tartrate/timolol should be discontinued.
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 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 their negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
As with systemic beta-blockers, if discontinuation of treatment is needed in patients with coronary heart disease, therapy should be withdrawn gradually to avoid rhythm disorders, myocardial infarct or sudden death.
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.
Brimonidine tartrate/timolol should be used with caution in patients with depression or cerebral insufficiency. In patients with severe renal impairment on dialysis, treatment with timolol has been associated with pronounced hypotension.
Respiratory disorders
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration some ophthalmic beta-blockers.
Brimonidine tartrate/timolol 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.
Surgical anaesthesia
Beta-blocking ophthalmological preparations may block the systemic beta-agonist effects e.g. of adrenaline. The anaesthesiologist should be informed when the patient is receiving timolol.
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. The indicatory signs of acute hypoglycaemia may be masked, in particular tachycardia, palpitations and sweating.
Beta-blockers may also mask the signs of hyperthyroidism.
Brimonidine tartrate/timolol 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 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.
The preservative in this medicinal product, benzalkonium chloride, may cause eye irritation. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Benzalkonium chloride is known to discolour soft contact lenses. Avoid contact with soft contact lenses.
Brimonidine tartrate/timolol has not been studied in patients with closed-angle glaucoma.
4.5 Interaction with other medicinal products and other forms of interaction
No specific drug interaction studies have been performed. Although specific drug interactions studies have not been conducted with brimonidine tartrate/timolol, the theoretical possibility of an additive or potentiating effect with CNS depressants (alcohol, barbiturates, opiates, sedatives, or anaesthetics) should be considered.
There is potential for additive effects resulting in hypotension, and/or marked bradycardia when ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, anti-arrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. After the application of brimonidine, very rare (<1 in 10,000) cases of hypotension have been reported. Caution is therefore advised when using brimonidine tartrate/timolol 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 section 4.4).
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 brimonidine tartrate/timolol.
Caution must be exercised if brimonidine tartrate/timolol 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 brimonidine tartrate/timolol 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 brimonidine tartrate/timolol, the theoretical possibility of an additive IOP lowering effect with prostamides, prostaglandins, carbonic anhydrase inhibitors and pilocarpine should be considered.
Concomitant administration of MAO inhibitors is contraindicated (see section 4.3). Patients who have been receiving MAOI therapy should wait 14 days after discontinuation before commencing treatment with brimonidine tartrate/timolol.
4.6 Fertility, pregnancy and lactation
Pregnancy
There are no adequate data for the use of brimonidine tartrate/timolol in pregnant women.
Brimonidine tartrate
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). The potential risk for humans is unknown.
Timolol
There are no adequate data for the use of timolol in pregnant women. It should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.
Epidemiological studies have not revealed malformative effects but show 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 brimonidine tartrate/timolol is administered until delivery, the neonate should be carefully monitored during the first days of life.
Brimonidine timolol/tartrate should not be used during pregnancy unless clearly necessary.
Breast-feeding
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.
It is not known if brimonidine is excreted in human milk but it is excreted in the milk of the lactating rat.
Brimonidine tartrate/timolol should not be used by women breast-feeding infants.
4.7 Effects on ability to drive and use machines
Brimonidine tartrate/timolol has minor influence on the ability to drive and use machines. It may cause transient blurring of vision, 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
Based on 12 month clinical data, the most commonly reported ADRs were conjunctival hyperaemia (approximately 15% of patients) and burning sensation in the eye (approximately 11% of patients). The majority of these cases was mild and led to discontinuation rates of only 3.4% and 0.5% respectively. Like other topically applied ophthalmic drugs, timolol is absorbed into the systemic circulation. This may cause similar undesirable effects to those seen with systemic beta-blocking agents. The incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
The following adverse drug reactions were reported during clinical trials:
Psychiatric disorders
Common (>1/100 to <1/10): depression
Nervous system disorders
Common (>1/100 to <1/10): somnolence, headache
Uncommon (>1/1000 to <1/100): dizziness, syncope
Eye disorders
Very common (>1/10):
Common (>1/100 to <1/10):
Uncommon (>1/1000 to <1/100):
conjunctival hyperaemia, burning sensation
stinging sensation in the eye, allergic conjunctivitis, corneal erosion, superficial punctuate keratitis, eye pruritus, conjunctival folliculosis, visual disturbance, blepharitis, epiphora, eye dryness, eye discharge, eye pain, eye irritation, foreign body sensation visual acuity worsened, conjunctival oedema, follicular conjunctivitis, allergic blepharitis, conjunctivitis, vitreous floater, asthenopia, photophobia, papillary hypertrophy, eyelid pain, conjunctival blanching, corneal oedema, corneal infiltrates, vitreous detachment
Cardiac disorders
Uncommon (>1/1000 to <1/100): congestive heart failure, palpitations
Vascular disorders Common (>1/100 to <1/10):
hypertension
Respiratory, thoracic and mediastinal disorders Uncommon (>1/1000 to <1/100): rhinitis, nasal dryness
Gastrointestinal disorders
Common (>1/100 to <1/10): oral dryness
Uncommon (>1/1000 to <1/100): taste perversion
Skin and subcutaneous tissue disorders
Common (>1/100 to <1/10): eyelid oedema, eyelid pruritus, eyelid
erythema
Uncommon (>1/1000 to <1/100): allergic contact dermatitis
General disorders and administration site conditions Common (>1/100 to to<1/10): asthenic conditions
Investigations
Common (>1/100 to <1/10): LFTs abnormal
The following adverse drug reactions have been reported since brimonidine tartrate/timolol has been marketed:
Cardiac disorders
Not known (cannot be estimated from the available data): arrhythmia, bradycardia, tachycardia
Vascular disorders
Not known (cannot be estimated from the available data): hypotension
Additional adverse events that have been seen with one of the components and may potentially occur also with the fixed combination:
Brimonidine
Psychiatric disorders: insomnia Eye disorders: iritis, miosis
Respiratory, thoracic and mediastinal disorders: upper respiratory symptoms, dyspnoea
Gastrointestinal disorders: gastrointestinal symptoms
General disorders and administration site conditions: systemic allergic reactions
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).
Timolol (further additional adverse reactions have been seen with ophthalmic beta-blockers and may _potentially occur with timolol)
Immune system disorders: systemic allergic reactions including angioedema, urticaria, localized and generalized rash, pruritus, anaphylactic reaction
Metabolism and nutrition disorders: hypoglycaemia Psychiatric disorders: insomnia, nightmares, memory loss
Nervous system disorders: cerebrovascular accident, increase in signs and symptoms of myasthenia gravis, paresthaesia, cerebral ischaemia
Eye disorders: decreased corneal sensitivity, blurred vision, diplopia, ptosis, choroidal detachment (following filtration surgery - see section 4.4), refractive changes (due to withdrawal of miotic therapy in some cases)
Ear and labyrinth disorders: tinnitus
Cardiac disorders: chest pain, oedema, atrioventricular block, cardiac arrest, cardiac failure
Vascular disorders: cerebrovascular accident, claudication, Raynaud's phenomenon, cold hands and feet
Respiratory, thoracic and mediastinal disorders: bronchospasm (predominantly in patients with pre-existing bronchospastic disease), dyspnoea, cough, respiratory failure
Gastrointestinal disorders: nausea, diarrhoea, dyspepsia, abdominal pain, vomiting Skin and subcutaneous tissue disorders: alopecia, psoriasiform rash or exacerbation of psoriasis; skin rash
Musculoskeletal and connective tissue disorders: myalgia, systemic lupus erythematosus
Renal and urinary disorders: Peyronie's disease
Reproductive system and breast disorders: sexual dysfunction, decreased libido
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
4.9 Overdose
Brimonidine
Ophthalmic overdose
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.
Systemic overdose resulting from accidental ingestion
Several reports of serious adverse events following inadvertent ingestion of brimonidine by paediatric subjects have been published or reported. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, hypotonia, bradycardia, hypothermia 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.
Two cases of adverse effects following inadvertent ingestion of 9-10 drops of brimonidine by adult subjects have been received. The subjects experienced a hypotensive episode, followed in one instance by rebound hypertension approximately 8 hours after ingestion. Both subjects were reported to have made a full recovery within 24 hours. No adverse effects were noted in a third subject who ingested an unknown amount of brimonidine orally.
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.
Timolol
Symptoms of systemic timolol overdose are: bradycardia, hypotension, bronchospasm, headache, dizziness and cardiac arrest. A study of patients showed that timolol did not dialyse readily.
If overdose occurs treatment should be symptomatic and supportive.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Ophthalmologicals - Antiglaucoma preparations and miotics - Beta-blocking agents - timolol, combinations ATC code: S01ED51
Mechanism of action
This fixed combination consists of two active substances: brimonidine tartrate and timolol maleate. 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. The fixed combinatino has a rapid onset of action.
Brimonidine tartrate is an alpha-2 adrenergic receptor agonist that is 1000-fold more selective for the alpha-2 adrenoceptor than the alpha-1 adrenoreceptor. This selectivity results in no mydriasis and the absence of vasoconstriction in microvessels associated with human retinal xenografts.
It is thought that brimonidine tartrate lowers IOP by enhancing uveoscleral outflow and reducing aqueous humour formation.
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 efficacy and safety
In three controlled, double-masked clinical studies, fixed-combination brimonidine tartrate/timolol (twice daily) produced a clinically meaningful additive decrease in mean diurnal IOP compared with timolol (twice daily) and brimonidine (twice daily or three times a day) when administered as monotherapy.
In a study in patients whose IOP was insufficiently controlled following a minimal 3-week run-in on any monotherapy, additional decreases in mean diurnal IOP of 4.5, 3.3 and 3.5 mmHg were observed during 3 months of treatment for fixed-combination brimonidine tartrate/timolol (twice daily), timolol (twice daily) and brimonidine (twice daily), respectively. In this study, at trough, a significant additional decrease in IOP could only be demonstrated on comparison with brimonidine but not with timolol, however a positive trend was seen with superiority at all other timepoints. In the pooled data of the other two trials statistical superiority versus timolol was seen throughout.
In addition, the IOP-lowering effect of fixed-combination brimonidine tartrate/timolol was consistently non-inferior to that achieved by adjunctive therapy of brimonidine and timolol (all twice daily).
The IOP-lowering effect of fixed-combination brimonidine tartrate/timolol has been shown to be maintained in double-masked studies of up to 12 months.
5.2 Pharmacokinetic properties
Fixed-combination brimonidine tartrate/timolol
Plasma brimonidine and timolol concentrations were determined in a crossover study comparing the monotherapy treatments to fixed-combination treatment with brimonidine tartrate and timolol in healthy subjects. There were no statistically significant differences in brimonidine or timolol AUC between the fixed combination and the respective monotherapy treatments. Mean plasma Cmax values for brimonidine and timolol following dosing with the fixed combination were 0.0327 and 0.406 ng/ml respectively.
Brimonidine
After ocular administration of 0.2% eye drops solution in humans, plasma brimonidine concentrations are low. Brimonidine is not extensively metabolised in the human eye and human plasma protein binding is approximately 29%. The mean apparent half-life in the systemic circulation was approximately 3 hours after topical dosing in man.
Following oral administration to man, brimonidine is well absorbed and rapidly eliminated. The major part of the dose (around 74% of the dose) was excreted as metabolites in urine within five days; no unchanged drug was detected in urine. In vitro studies, using animal and human liver, indicate that the metabolism is mediated largely by aldehyde oxidase and cytochrome P450. Hence, the systemic elimination seems to be primarily hepatic metabolism.
Brimonidine binds extensively and reversibly to melanin in ocular tissues without any untoward effects. Accumulation does not occur in the absence of melanin. Brimonidine is not metabolised to a great extent in human eyes.
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 7 hours. Timolol is partially metabolised by the liver with timolol and its metabolites excreted by the kidney. Timolol is not extensively bound to plasma protein.
5.3 Preclinical safety data
The ocular and systemic safety profile of the individual components is well established. 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. Additional ocular repeated dose toxicity studies on fixed-combination brimonidine tartrate/timolol also showed no special hazard for humans.
Brimonidine
Brimonidine tartrate did not cause any teratogenic effects in animals, but caused abortion in rabbits and postnatal growth reduction in rats at systemic exposures approximately 37-times and 134-times those obtained during therapy in humans, respectively.
Timolol
In animal studies, beta-blockers have been shown to produce reduced umbilical blood flow, reduced fetal growth, delayed ossification and increased fetal and postnatal death, but no teratogenicity. With timolol, embryotoxicity (resorption) in rabbit and fetotoxicity (delayed ossification) in rats have been seen at high maternal doses. Teratogenicity studies in mice, rats and rabbits, at oral doses of timolol up to 4200 times of that in the human daily dose of fixed-combination brimonidine tartrate/timolol, showed no evidence of fetal malformation.
6.1 List of excipients
Benzalkonium chloride
Sodium dihydrogen phosphate dihydrate
Disodium phosphate dihydrate
Hydrochloric acid or sodium hydroxide to adjust pH
Water for injections
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
Unopened bottle:
18 months.
After first opening:
Use within 28 days.
Chemical and physical in-use stability has been demonstrated for 28 days when stored below 30°C and kept in outer carton to protect from light.
From a microbiological point of view, once opened, the product may be stored for a maximum of 28 days when stored below 30°C and kept in outer carton to protect from light. Other in-use storage times and conditions are the responsibility of the user.
6.4 Special precautions for storage
Store below 30 °C. Keep the bottle in the outer carton to protect from light. For storage conditions of the finished product after first opening, see section 6.3.
6.5 Nature and contents of container
White low density polyethylene bottles with a low density polyethylene dropper and a high density polyethylene tamper proof orange screw cap. Each bottle has a fill volume of 5 ml.
The following pack sizes are available: cartons containing 1, 3, 5, 6 or 10 bottles of 5 ml. Not all pack sizes may be marketed.
6.6 Special precautions for disposal
No special requirements.
7
MARKETING AUTHORISATION HOLDER
TEVA UK Limited,
Brampton Road,
Hampden Park,
Eastbourne,
East Sussex BN22 9AG United Kingdom
8
9
02/11/2016