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Sterile ophthalmic solution containing levobunolol hydrochloride 5.0 mg/mL (0.5%), with 0.04mg/mL benzalkonium chloride as preservative.[HC1].
Levobunolol HCl is a noncardioselective β-adrenoceptor blocking agent, equipotent at both β1 and β2 receptors. Levobunolol HCl is greater than 60 times more potent than its dextro isomer in its β-blocking activity, yet equipotent in its potential for direct myocardial depression. Accordingly, the levoisomer, levobunolol HCl, is used. Levobunolol HCl does not have significant local anaesthetic (membrane stabilising) or intrinsic sympathomimetic activity.
β-Adrenergic receptor blockade reduces cardiac output in both healthy subjects and patients with heart disease. In patients with severe impairment of myocardial function, β-adrenergic receptor blockade may inhibit the stimulatory effect of the sympathetic nervous system necessary to maintain adequate cardiac function.
β-Adrenergic receptor blockade in the bronchi and bronchioles results in increased airway resistance from unopposed parasympathetic activity. Such an effect in patients with asthma or other bronchospastic conditions is potentially dangerous.
Levobunolol HCl has been shown to be an active agent in lowering elevated as well as normal intraocular pressure (IOP) whether or not accompanied by glaucoma. Elevated IOP presents a major risk factor in glaucomatous field loss. The higher the level of IOP, the greater the likelihood of optic nerve damage and visual field loss.
In several controlled clinical studies of four years duration, intraocular pressure was well controlled in the majority of subjects treated with 0.5% levobunolol HCl twice a day, with annual retention rates of over 80%. The mean IOP decrease from baseline was between 5.8 mmHg and 7.8 mmHg. A total of 72 subjects remained on this agent over the entire four years treatment. No significant effects on pupil size, tear production or corneal sensitivity was observed in any of these studies. Levobunolol HCl at the concentrations tested, when applied topically, decreased heart rate and blood pressure in some patients. Efficacy was at least comparable to that of timolol over the entire study period.
The onset of action with one drop of levobunolol HCL can be detected within one hour after treatment, with maximum effect seen between 2 and 6 hours. A significant decrease in IOP can be maintained for up to 24 hours following a single dose.
The primary mechanism of the ocular hypotensive action of levobunolol HCl in reducing IOP appears to be a decrease in aqueous humor production. Levobunolol HCl reduces IOP with little or no effect on pupil size or accommodation in contrast to the miosis which cholinergic agents are known to produce. The blurred vision and night blindness often associated with miotics would not be expected and have not been reported with the use of levobunolol HCl. This is particularly important in cataract patients with central lens opacities who would experience decreased visual acuity with pupillary constriction.
Control of intraocular pressure in patients with open angle glaucoma.
Control of ocular hypertension.
Treatment of acute increased intraocular pressures following laser capsulotomy and extra-capsular cataract extraction.
The recommended starting dose is one drop of levobunolol HCl 0.5% in the affected eye(s) twice a day. Careful monitoring of patients is advised, particularly in the first few days after starting treatment or if the dose of levobunolol HCl is increased.
In some patients, the IOP-lowering response to Levobunolol HCl Eye Drops 0.5% may require a few weeks to stabilise. Intraocular pressure should therefore be measured approximately 4 weeks after treatment is initiated[HC2].
Dosages above one drop of levobunolol HCl 0.5% twice daily are not generally more effective. If the patient's IOP is not at a satisfactory level on this regimen, concomitant therapy with dipivefrine and/or adrenaline, and/or pilocarpine and other miotics, and/or systemically administered carbonic anhydrase inhibitors, such as acetozolamide, can be instituted.
If the intraocular pressure has been maintained at a satisfactory level the attending physician may determine that in certain cases the instillation of one drop in the affected eye(s) once a day is sufficient for treatment.
Levobunolol HCl is contraindicated in those individuals with bronchial asthma or with a history of bronchial asthma or severe chronic obstructive pulmonary disease (see Warnings and Precautions); sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure (see Warnings and Precautions); cardiogenic shock; or hypersensitivity to any component of this product.
Levobunolol HCl should be used with caution in patients with known hypersensitivity to other β-adrenergic blocking agents.
Use with caution in patients with known diminished pulmonary function.
In patients with angle-closure glaucoma, the immediate objective of treatment is to re-open the angle. This requires, in most cases, constricting the pupil with a miotic. Levobunolol HCl has little or no effect on the pupil. When levobunolol HCl is used to reduce elevated intraocular pressure in angle-closure glaucoma, it should be followed by a miotic and not used alone.
As levobunolol HCl contains benzalkonium chloride, it should not be used in patients who continue to wear hydrophyllic (soft) contact lenses[HC3].
As with other topically applied ophthalmic drugs, levobunolol HCl may be absorbed systemically. The same adverse reactions found with systemic administration of β-adrenergic blocking agents may occur with topical administration. For example, severe respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma, and rarely death in association with cardiac failure, have been reported with topical application of β-adrenergic blocking agents (see Contraindications).
Foetotoxicity (as evidence by a greater number of resorption sites) has been observed in rabbits when doses of levobunolol HCl equivalent to 200 and 700 times the recommended dose for the treatment of glaucoma were given. No foetotoxic effects have been observed in similar studies with rats at up to 1800 times the human dose for glaucoma. Teratogenic studies with levobunolol in rats at doses up to 25 mg/kg/day (1800 times the recommended human dose for glaucoma) showed no evidence of foetal malformations. There were no adverse effects on postnatal development of offspring. It appears when results from studies using rats and studies with other beta-adrenergic blockers are examined, that the rabbit may be a particularly sensitive species. There are no adequate and well-controlled studies in pregnant women. Levobunolol HCl should be used during pregnancy only if the potential benefit justifies the potential risk to the foetus.
It is not known whether the drug is excreted in human milk. Systemic β-blockers and topical timolol maleate are known to be excreted in human milk. Caution should be exercised when levobunolol HCl is administered to a nursing woman.
Safety and effectiveness in children have not been established.
In a lifetime study of mice there were statistically significant (p <= 0.05) increases in the incidence of benign leiomyomas in female mice at 200 mg/kg/day (14,000 times the maximum recommended human dose for glaucoma), but not at 12 or 50 mg/kg/day (850 and 3,500 times the human dose). In a two-year oral study of levobunolol HCl in rats there was a statistically significant (p <= 0.05) increase in the incidence of hepatomas in male rats administered 12,800 times [HC4]the recommended human dose for glaucoma. Similar differences were not observed in rats administered oral doses equivalent to 350 times to 2,000 times the recommended human dose for glaucoma.
Levobunolol did not show evidence of mutagenic activity in a battery of microbiological and mammalian in vitro and in vitro assays. Reproduction and fertility studies in rats showed no adverse effects on male or female fertility at doses up to 1,800 times the recommended human dose for glaucoma.
Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition by β-adrenergic receptor blockade may precipitate more severe failure.
Continued depression of the myocardium with β-blocking agents over a period of time can, in some cases, lead to cardiac failure. At the first sign of symptom of cardiac failure, levobunolol HCl should be discontinued.
In patients with non-allergic bronchospasm or with a history of non-allergic bronchospasm, (e.g. chronic bronchitis, emphysema), levobunolol HCl should be administered with caution since it may block bronchodilation produced by endogenous and exogenous catecholamine stimulation of β2-receptors.
The necessity or desirability of withdrawal of β-adrenergic blocking agents prior to major surgery is controversial. β-Adrenergic blockade impairs the ability of the heart to respond to β-adrenergically mediated reflex stimuli. This may augment the risk of general anaesthesia in surgical procedures. Some patients receiving β-adrenergic blocking agents have been subject to protracted severe hypotension during anaesthesia. For these reasons, in patients undergoing elective surgery, gradual withdrawal of β-adrenergic blocking agents may be appropriate.
If necessary during surgery, the effects of β-adrenergic blocking agents may be reversed by sufficient doses of such agonists as isoprenaline, dopamine, dobutamine or noradrenaline acid tartrate (see Overdosage).
β-Adrenergic blocking agents should be administered with caution to patients subject to spontaneous hypoglycaemia or to diabetic patients (especially those with labile diabetes) who are receiving insulin or oral hypoglycaemic agents. β-Adrenergic blocking agents may mask the signs and symptoms of acute hypoglycaemia.
β-Adrenergic blocking agents may mask certain clinical signs (e.g. tachycardia) of hyperthyroidism. Patients suspected of developing thyrotoxicosis should be managed carefully to avoid abrupt withdrawal of β-adrenergic blocking agents which might precipitate a thyroid storm.
Contains sodium metabisulfite, a sulfite which may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic rather than in non-asthmatic people[HC5].
β-Adrenergic blockade has been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness).
Although levobunolol HCl used alone has little or no effect on pupil size, mydriasis resulting from concomitant use of levobunolol HCl and adrenaline may occur.
Close observation of the patient is recommended when a β-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, because of possible additive effects and the production of hypotension and/or marked bradycardia, which may produce vertigo, syncope or postural hypotension.
No adverse ocular effects were observed in rabbits administered with levobunolol HCl topically in studies lasting one year in concentrations up to 10 times the human dose concentration.
The following adverse effects have been reported rarely with the use of levobunolol HCl: iridocyclitis, headache, transient ataxia, dizziness, lethargy, urticaria and pruritis.
Decreased corneal sensitivity has been noted in a small number of patients. Although levobunolol has minimal membrane-stabilising activity, there remains the possibility of decreased corneal sensitivity after prolonged use.
The following additional adverse reactions have been reported with ophthalmic use of β1 and β2 (non-selective) adrenergic blocking agents:
Headache.
Arrhythmia, syncope, heart block, cerebral vascular accident, cerebral ischaemia, congestive heart failure, palpitation.
Nausea.
Depression.
Hypersensitivity, including localised and generalised rash.
Bronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure.
Masked symptoms of hypoglycaemia in insulin-dependent diabetics (see Warnings and Precautions).
Signs and symptoms of keratitis, blepharitis, visual disturbances including refractive changes (due to withdrawal of miotic therapy in some cases), diplopia, ptosis.
Other reactions associated with the oral use of non-selective adrenergic blocking agents should be considered potential effects with ophthalmic use of these agents.
In clinical trials the use of levobunolol HCl has been associated with transient ocular burning and stinging in about 1 in 3 patients, and blepharoconjunctivitis in about 1 in 20 patients. Decreases in heart rate and blood pressure have been reported (see Contraindications and Warnings and Precautions).
Levobunolol HCl should be used with caution in patients who are receiving a β-adrenergic receptor blocking agent orally, because of the potential for additive effects on systemic β-blockade.
No data are available regarding overdosage in humans. Should accidental ocular overdosage occur, flush eye(s) with water or normal saline. If accidentally ingested, efforts to decrease further absorption may be appropriate (gastric lavage).
The most common signs and symptoms to be expected with overdosage of a systemic β-adrenergic blocking agent are symptomatic bradycardia, hypotension, bronchospasm and acute cardiac failure. Should these symptoms occur, discontinue levobunolol HCl therapy and initiate appropriate supportive therapy. The following supportive measures should be considered:
Store below 25°C. Protect from light. Do not freeze.
Discard unused contents 4 weeks after opening. Contents are sterile if seal is intact.
Prescription Medicine.
5 mL eye drops, dropper bottles, 5 mg/mL (0.5%).
Levobunolol hydrochloride is a β-adrenergic receptor blocking agent. Chemical name: (-)-5-(3-(tert-butylamino-2-hydroxypropoxy)-3,4-dihydro-1(2H)-naphthalenone hydrochloride.
Alcon Laboratories
Distributed in New Zealand by:
Pacific Pharmaceuticals Ltd
PO Box 11-183
Ellerslie
AUCKLAND
Telephone: 09-579-2792
31 January 2000.