1 ml suspension contains 2.5 mg betaxolol base (equivalent to 2.8 mg betaxolol hydrochloride).
Excipient with known effect: 1 ml suspension contains 0.1 mg benzalkonium chloride.
Excipients/Inactive Ingredients: Benzalkonium chloride, Mannitol, Poly(styrene-divinyl benzene) Sulfonic Acid, Carbomer 974P, Disodium Edetate, N-lauroylsarcosine, Boric acid, Concentrated hydrochloric acid and/or sodium hydroxide (to adjust pH), Purified water.
Pharmacotherapeutic Group: Anti-glaucoma preparations and miotics, beta-blocking agents. ATC Code: S 01 ED 02.
Betaxolol hydrochloride is a cardioselective beta-blocker of the beta-adrenergic receptors. It does not have local anaesthetic (membrane-stabilising) activity and is devoid of sympathicomimetic intrinsic action.
In an in vivo study in dogs, it was demonstrated that betaxolol causes a decrease in the total peripheral vascular resistance, which may be attributed to a peripheral vasorelaxing action. After topical administration, betaxolol would cause a local constriction of the ciliary arterioles of rabbits. However, this effect decreases after administration during 50 days. Various in vitro studies, where use has been made of ocular and non-ocular vessels of rat, guinea pig, rabbit, canine, porcine and bovine models indicate, however, a vasorelaxing and calcium channel blocking action of betaxolol. An experimental study indicates the neuroprotective action of betaxolol in an in vivo induced acute ocular hypertension in rats, and in vitro on the retina of rabbit, cortical cultures of rat and retinal cultures of rabbit.
BETOPTIC S Suspension 2.5 mg/ml eye drops provides IOP lowering activity equivalent to that demonstrated by BETOPTIC Solution 5 mg/ml eye drops.
Elevated intraocular pressure presents a major risk factor in glaucomatous field loss. The higher the level of intraocular pressure, the greater the likelihood of optic nerve damage and visual field loss. Upon instillation in the eye, betaxolol has the action of reducing elevated as well as normal intraocular pressure, and the mechanism of ocular hypotensive action appears to be a reduction of ocular aqueous production as demonstrated by tonography and fluorophotometry. The onset of action of betaxolol can generally be noted within 30 minutes and the maximal effect can usually be detected 2 hours after topical administration. A single dose provides a 12-hour reduction in intraocular pressure.
Data obtained during controlled studies in patients with chronic open-angle glaucoma and ocular hypertension suggest that treatment with betaxolol has a possible superior long-term effect on visual field when compared to treatment with timolol, a non-selective beta-blocker. There is, furthermore, evidence that betaxolol could maintain or improve the ocular blood flow/perfusion.
Topically administered ophthalmic betaxolol, has little or no effect on the constriction of the pupil and minimal effect on pulmonary and cardiovascular parameters.
The polar nature of betaxolol can produce apparent ocular irritation.
In this formulation, betaxolol molecules are ionically bound to the amberlite resin. Upon instillation, the betaxolol molecules are displaced by sodium ions in the tear film. This displacement process occurs over several minutes and enhances the ocular comfort observed for BETOPTIC S Suspension.
Topically administered betaxolol, may be resorbed systemically and may cause the same undesirable effects as when orally administered (see Adverse Reactions).
Orally administered beta-adrenergic blocking agents reduce cardiac output in healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac function.
Betaxolol has no significant effect on the pulmonary function, as measured by the Forced Expiratory Volume per Second (FEV1), the Forced Vital Capacity (FVC) and the relation between them (FEV1/FVC).
No evidence of cardiovascular beta-adrenergic blockade during exercise was observed.
Lifetime studies with betaxolol have been completed in mice at oral doses of 6, 20 or 60 mg/kg/day and in rats at 3, 12 or 48 mg/kg/day. Betaxolol hydrochloride did not have any carcinogenic effects. Higher dose levels were not tested.
In a variety of in vitro and in vivo essays on bacteria and mammalian cells, no mutagenic effects caused by betaxolol were observed.
Paediatric population: There are only limited data available on the use of betaxolol 0.25% in the paediatric population for a treatment period up to 12 weeks. One small, double-blind, randomised, published clinical study conducted on 105 children (n=34 for betaxolol) aged 12 days - 5 years show to some extent evidence that betaxolol in the indication primary congenital and primary juvenile glaucoma is effective in short-term treatment.
Pharmacokinetics: The onset of betaxolol's effect is usually within 30 minutes from administration with its maximum being 2 hours after administration. A single dose reduces the intraocular pressure for the period of 12 hours.
After local ocular administration, betaxolol is absorbed systemically with a mean maximal plasma concentration of 1.1 ± 0.8 ng/ml. Systemic absorption and symptoms of the same undesirable effects as in the case of its oral administration may occur (see Adverse Reactions).
Paediatric population: After topical administration in the eyes betaxolol is absorbed and reaches systemic circulation. In adults receiving a 40 μl dose of 0.5% betaxolol solution a mean maximum plasma concentration of 0.1 ± 0.8 ng/ml was observed.
Due to a smaller distribution volume in children compared to adults a higher circulation concentration has to be taken into account. Because betaxolol elimination is primarily achieved by metabolisation, the immature metabolic enzyme pathways in neonates may result in an increased elimination half-life and increased blood levels with a greater risk of adverse events.
Toxicology: Preclinical safety data: Preclinical data reveal no special hazard for humans based on studies of repeated dose toxicity, genotoxicity and carcinogenic potential.
After oral administration of betaxolol in rats embryofoetal developmental toxicity was observed in the presence of maternal toxicity. Orally administered betaxolol in rats resulted in early and late resorptions but did not demonstrate teratogenicity. These effects were only observed with doses far exceeding the recommended ophthalmic dose in humans and are therefore of minor relevance to clinical use.
BETOPTIC S Suspension has been shown to be effective in lowering intraocular pressure and may be used in patients with chronic open-angle glaucoma and ocular hypertension. It may be used alone or in combination with other intraocular pressure lowering medications.
Adults (including elderly): The usual dose is one drop of BETOPTIC S Suspension in the treated eye(s), twice daily.
In some patients, the intraocular pressure lowering response may require a few weeks to stabilize. The intraocular pressure should therefore be determined during the first month of treatment.Thereafter, the frequency of measurement should be determined by the physician. Because of variations of intraocular pressure in some patients, satisfactory response to twice a day therapy is best determined by measuring intraocular pressure at different times during the day.
If the intraocular pressure of the patient is not adequately controlled on this regimen, concomitant therapy with other intraocular pressure lowering medications (including pilocarpine, other miotics, adrenaline or systemically administered carbonic anhydrase inhibitors) can be instituted.
Paediatric population: Due to limited data, betaxolol can only be recommended for use in primary congenital and primary juvenile glaucoma for a transitional period while a decision is made on a surgical approach and in case of failed surgery while considering further options.
The physician should carefully assess the risks and benefits when considering betaxolol therapy in paediatric patients. A detailed paediatric history and examination to determine the presence of systemic abnormalities should precede the use of betaxolol.
No specific dosage recommendation can be made as there are only limited clinical data (see Pharmacology: Pharmacodynamics under Actions). However, if the benefit outweighs the risk, it is recommended to use the lowest active agent concentration available once daily. If the IOP cannot be sufficiently controlled, careful up-titration to a maximum of 2 drops daily per affected eye has to be considered. If applied twice daily, an interval of 12 hours between administrations should be preferred.
Furthermore the patients, especially newborn infants, should be carefully observed after administration of the first dose for 1 to 2 hours in the ophthalmologist's office/hospital and monitored closely for ocular and systemic side effects until surgery is performed.
Duration of treatment: Temporary use in paediatric population (see Paediatric population previously).
Method of administration: Shake well before use.
Nasolacrimal occlusion or closure of the eyelids for 2 minutes decreases the systemic absorption. This may result in reduced systemic side effects and increased local activity.
Use in hepatic and renal impairment: The safety and efficacy of BETOPTIC S Suspension eye drops in patients with hepatic and renal impairment have not been established.
If ocular overdosage occurs, flush eye(s) with water or normal saline (sodium chloride solution 0.9%).
The most common signs and symptoms of overdosage from systemic beta-blockers are bradycardia, hypotension, bronchospasm and acute cardiac failure. If these occur, discontinue therapy and initiate appropriate supportive therapy.
Hypersensitivity to the active substance, or to any of the excipients listed in Description.
Reactive airway disorders, including severe bronchial asthma or a history of severe bronchial asthma, severe chronic obstructive pulmonary disease.
Patients with sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pacemaker, known cardiac failure, cardiogenic shock.
General: For ocular use only. Not for injection or ingestion.
Like other topically applied ophthalmic agents, betaxolol is absorbed systemically. Due to its beta-adrenergic component, betaxolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. Incidence of systemic undesirable effects after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see Dosage & Administration.
After application of the eye drops, following measures are useful to reduce systemic resorption: Keep the eyelid closed for 2 minutes.
Close the lachrymal duct with the finger for 2 minutes.
Cardiac disorders: Use with caution in patients with uncontrolled heart failure. When beginning therapy with betaxolol, patients with a history of severe cardiac disease should be monitored closely for signs of cardiac failure. Treatment with BETOPTIC S Suspension should be discontinued at the first signs of cardiac failure.
In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions.
Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block.
Vascular disorders: Because of potential effects of beta-blockers on blood pressure and pulse (e.g. hypotension, bradycardia), use with caution in patients with cerebrovascular insufficiency, untreated phaeochromocytoma or metabolic acidosis, since beta-adrenergic blocking agents can adversely affect such diseases. If signs or symptoms suggesting reduced cerebral blood flow develop, consider alternative therapy.
Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Hypoglycaemia/diabetes mellitus: 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.
Thyrotoxicosis: Patients having or suspected of developing thyrotoxicosis should be monitored closely during ophthalmic betaxolol therapy, since β-blocking agents may mask certain signs (e.g. tachycardia) and symptoms of hyperthyroidism and abrupt withdrawal of these agents can precipitate thyroid storm.
Respiratory disorders: Caution should be exercised in the treatment of glaucoma patients with excessive restriction of pulmonary function. There have been reports of asthmatic attacks and pulmonary distress during betaxolol treatment.
Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers.
Patients with mild/moderate bronchial asthma, a history of mild/moderate bronchial asthma or, mild/moderate chronic obstructive pulmonary disease (COPD) should be treated with caution.
Although rechallenges of some such patients with ophthalmic betaxolol has not adversely affected pulmonary function test results, the possibility of adverse pulmonary effects in patients sensitive to beta-blockers cannot be ruled out.
The risk of inducing bronchospasm must be appreciated in patients with symptomatic or poorly controlled asthma or obstructive airway diseases. Appropriate precautions, including consideration of alternative glaucoma therapies, should be taken.
Corneal diseases: Ophthalmic beta-blockers may induce dryness of eyes. Patients with corneal diseases should be treated with caution.
Muscle weakness: Beta-adrenergic receptor inhibitors have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalized weakness).
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 betaxolol.
Consideration should be given to the gradual withdrawal of beta-adrenergic receptor blocking agents prior to general anaesthesia because of reduced ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli.
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 doses 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.
Other β-blocking agents: Betaxolol may interact with other medicinal products (see Interactions). The effect on intraocular pressure or the known effects of systemic beta-blockade may be potentiated when betaxolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents is not recommended (see Interactions).
Ocular: When BETOPTIC S Suspension is used to reduce elevated intraocular pressure in closed angle glaucoma, it should be used with a miotic and not alone. In patients with closed angle glaucoma, the immediate treatment objective is to reopen the angle by constriction of the pupil with a miotic agent. Betaxolol has little or no effect on the pupil.
Paediatric patients: In general, Betaxolol solutions should be used with caution in young glaucoma patients (see Pharmacology: Pharmacokinetics under Actions).
It is important that parents are informed about possible adverse reactions so they can stop treatment immediately. Possible signs are e.g. cough or wheezy breathing.
Betaxolol should be used with extreme caution in neonates, infants and young children.
Contact lenses: BETOPTIC S Suspension eye drops contains a preservative, benzalkonium chloride, which may cause irritation and is known to discolour soft contact lenses. Avoid contact with soft contact lenses.
Patients must be instructed to remove contact lenses prior to application of BETOPTIC S Suspension and wait at least 15 minutes before reinsertion of the lenses.
Effects on ability to drive and use machines: BETOPTIC S Suspension eye drops has no or negligible influence on the ability to drive and use machines.
However, as with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines.
If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.
Pregnancy: There are no adequate data for the use of betaxolol in pregnant women. 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. Studies in animals have shown reproductive toxicity (see Pharmacology: Toxicology: Preclinical safety data under Actions). Betaxolol should not be used during pregnancy unless clearly necessary. To reduce systemic absorption, see Dosage & Administration.
If BETOPTIC S Suspension is administered until delivery, the neonate should be carefully monitored during the first days of life.
Lactation: Beta-blockers and systemically administered betaxolol are excreted in breast milk. However, at therapeutic doses of betaxolol 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 Dosage & Administration.
It is unknown whether betaxolol is excreted to human milk following topical ocular administration.
However, a risk to the suckling child cannot be excluded.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from betaxolol therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.
Fertility: There are no data available concerning the effect of BETOPTIC S Suspension eye drops on fertility.
Summary of the safety profile:
In clinical trials, the most frequent adverse reaction associated with use of eye drops containing betaxolol has been transient ocular discomfort.
Tabulated summary of adverse reactions:
Like other topically applied ophthalmic drugs, betaxolol is absorbed into the systemic circulation. This may cause similar undesirable effects as seen with systemic beta-blocking agents. Incidence of systemic ADRs after topical ophthalmic administration is lower than for systemic administration. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers.
The following adverse reactions are classified according to 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 <1,000), very rare (<1/10,000), or not known (cannot be estimated from the available data). Within each frequency-grouping, adverse reactions are presented in order of decreasing seriousness. The adverse reactions were obtained from clinical trials and postmarketing spontaneous reports. (See Table 1.)
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Additional adverse reactions have been seen with ophthalmic beta-blockers and may potentially occur with BETOPTIC S Suspension. (See Table 2.)
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Description of selected adverse reactions:
Since topically applied beta-adrenergic blocking agents may be absorbed systemically, adverse reactions found with systemic administration of beta1-adrenergic blocking agents may occur with topical administration. These may include bradycardia, a slowed AV (atrioventricular) conduction or increase of an existing AV-block, hypotension, heart failure, cold and cyanotic extremities, Raynauds phenomenon, paraesthesia of the extremities, increase of an existing intermittent claudication, fatigue, headaches, impaired vision, hallucinations, psychoses, confusion, impotence, dizziness, sleep disturbances, depression, nightmares, gastro-intestinal problems, nausea, vomiting, diarrhoea, bronchospasm in patients with bronchial asthma or a history of asthmatic complaints, disorder of the skin, especially rash, and dry eyes. Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia.
The safety and IOP-lowering effect of Betoptic 0.25% has been demonstrated in paediatric patients in a 3-month, multi-centre, double-masked, active-controlled trial. The adverse drug reaction profile of Betoptic 0.25% was comparable to that seen in adult patients.
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.
No specific drug interaction studies have been performed with betaxolol.
Each interaction that is associated with systemically administered beta-blockers can, in principle, appear with the use of beta-blocker eye drops.
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, or beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine (see Precautions). Orally administered beta-adrenergic blocking agents reduce cardiac output in healthy subjects and in patients with heart disease. In patients with severe impairment of myocardial function, beta-adrenergic receptor antagonists may inhibit the sympathetic stimulatory effect necessary to maintain adequate cardiac function.
Coadministration of ophthalmic beta-blockers with digitalis may have additive effects in prolonging atrioventricular conduction time. Close observation of the patient is recommended when a beta-adrenergic receptor inhibitor is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or bradycardia which may result in vertigo, syncope or postural hypotension.
When used in conjunction with topical miotics and/or systemically administered carbonic anhydrase inhibitors, the effect of betaxolol eye drops in lowering IOP may be additive. In patients with angle-closure glaucoma, the immediate treatment consists in re-opening the angle by constriction of the pupil with a miotic agent. Betaxolol has little or no effect on the pupil. Therefore, betaxolol eye drops should be used simultaneously with a miotic to reduce elevated intraocular pressure in angle-closure glaucoma (see Precautions).
Ophthalmic beta-blockers and Phenothiazine compounds may have potential additive hypotensive effects due to mutual inhibition of metabolism.
Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see Precautions).
Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.
If supplementary eye preparations are to be used, one should wait at least 5 minutes between two applications. Eye ointments should be administered last.
Incompatibilities: Not applicable.
Special Precautions for disposal and other handling: No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
Shelf life: Discard 4 weeks after first opening.
S01ED02 - betaxolol ; Belongs to the class of beta blocking agents. Used in the treatment of glaucoma.
Eye susp 0.25% (white to off-white) x 5 mL.