Description: Levobunolol is an ophthalmic beta-blocker. It is "nonselective" (i.e., equally effective at beta1- and beta2-receptor sites). Levobunolol is the levorotatory isomer of bunolol, which is structurally similar to propranolol. Levobunolol has a 60-fold and 3-fold greater potency compared with the dextrorotatory isomer and the racemic compound, respectively. Only the levo isomer is used clinically as an ophthalmic agent for the treatment of increased IOP due to open-angle glaucoma or ocular hypertension. Levobunolol was approved by the FDA in December 1985. Another ophthalmic formulation (Beta-Site�) is nearing the end of phase III investigation. Mechanism of Action: Although levobunolol's exact mechanism of action has not been fully determined, it is believed to be due to a reduction of the production of aqueous humor via inhibition of adrenergically driven processes within the ciliary processes. As a result of levobunolol's actions, IOP is reduced in patients with either elevated or normal IOP. This reduction occurs irrespective of the presence of glaucoma. Visual acuity, pupil size, and accommodation do not appear to be affected by levobunolol. Because levobunolol has no effect on pupil size, it should be used only in conjunction with a topical miotic, such as pilocarpine, to reduce IOP in patients with angle-closure glaucoma. Levobunolol has the capacity to decrease the IOP in the contralateral, untreated eye to a lesser extent than in the treated eye. Delayed tolerance to the effects of levobunolol can occur after >2 years of continuous use. Levobunolol does not possess local anesthetic or intrinsic sympathomimetic activity. Several mechanisms of action have been proposed to explain the systemic effects of beta-blockers. Beta-adrenergic antagonists counter the effect of sympathomimetic neurotransmitters (i.e., catecholamines) by competing for receptor sites. Similar to propranolol and timolol, levobunolol blocks sympathetic stimulation mediated by beta1-adrenergic receptors in the heart and vascular smooth muscle. The pharmacodynamic consequences of this activity can be reduced resting and exercise heart rate (and subsequently cardiac output) and reduced systolic and diastolic blood pressure. Reflex orthostatic hypotension also may be reduced. In addition, levobunolol can competitively block beta2-adrenergic responses in the bronchial smooth muscle, potentially inducing bronchospasm. Pharmacokinetics: Little is known about many of the specific pharmacokinetic parameters of levobunolol. Most of what is known reflects the clinical observation of anticipated pharmacodynamic responses. Following application to the eye, an unquantified degree of systemic absorption occurs as evidenced by changes in both cardiac and pulmonary performance, which are expected to occur in response to systemic beta-blockade. The extent of topical absorption has not been elucidated. Other markers of absorption include a reduction in IOP, which is usually seen within 1 hour and reaches a maximum in 2�6 hours. The duration of action of levobunolol is 12�24 hours. Patients treated for open-angle glaucoma or ocular hypotension require about 2�3 weeks of continuous treatment to achieve maximum therapeutic benefit from levobunolol. The distribution of levobunolol has not been determined. The metabolism of levobunolol following ophthalmic application has not been clearly determined. Extensive metabolism occurs in the liver to produce multiple metabolites, of which one, dihydrolevobunolol, has beta-adrenergic blocking activity approximately 65% of that of the parent drug. Levobunolol and its metabolites are subsequently glucuronidated and presumably excreted in the urine and feces. Indications...Dosage For the treatment of chronic open-angle glaucoma or ocular hypertension: Ophthalmic dosage: Adults: Instill 1�2 drops of the 0.25% preparation in the affected eye(s) twice daily, or instill 1�2 drops of the 0.5% preparation in the affected eye(s) once daily. A dosage greater than 1 drop of the 0.5% preparation twice daily generally does not further reduce intraocular pressure (IOP) and is not recommended. If the patient's IOP is not controlled, concomitant therapy with alternative agents may be considered. Elderly: See adult dosage. Children, infants, and neonates: Safe and effective use has not been established. Maximum Dosage Limits: �Adults: 2 drops/day levobunolol 0.5% or 4 drops/day of 0.25% ophthalmic solution in the affected eye(s). �Elderly: 2 drops/day levobunolol 0.5% or 4 drops/day of 0.25% ophthalmic solution in the affected eye(s). �Adolescents: Safe and effective use has not been established. �Children: Safe and effective use has not been established. Patients with hepatic impairment: No dosage adjustment is needed. Intermittent hemodialysis: No dosage adjustment is needed. Patients with renal impairment: No dosage adjustment is needed. Ophthalmic Administration �Instruct patient on proper instillation of eye solution (see Patient Information). �Do not to touch the tip of the dropper to the eye, fingertips, or other surface. Contraindications As levobunolol has been shown to be absorbed systemically, all of the precautions and contraindications pertaining to systemically-administered beta-blockers should be carefully considered prior to using levobunolol. Levobunolol should not be used in patients with preexisting cardiac disease, such as severe bradycardia, advanced AV block, cardiogenic shock, coronary artery disease, vasospastic angina, or overt congestive heart failure, particularly those with severe left ventricular dysfunction. Rare deaths have been reported in patients at high risk for cardiac or pulmonary complications secondary to treatment with beta-blockers. Beta-blockers should be used with caution in patients with a pheochromocytoma if effective blockade of alpha and beta receptors is not achieved, because of the risk of hypertension. beta-blockers should be used with caution in patients with hyperthyroidism or thyrotoxicosis because the drug can mask tachycardia, which is a useful monitoring parameter in thyroid disease. Abrupt withdrawal of beta-blockers in a patient with hyperthyroidism can precipitate thyroid storm. Note that beta-blockers are, in general, useful in treating hyperthyroid-related states. Although levobunolol is administered ophthalmically, the potential of systemic adverse reactions still exists. Levobunolol should be used with caution in patients with diabetes mellitus because the drug can mask symptoms of hypoglycemia such as tachycardia, palpitations, blood pressure changes, tremor, and anxiety. Use levobunolol with caution in patients with asthma or other pulmonary disease in which acute bronchospasm would put them at risk (e.g., COPD, emphysema, bronchitis). Ophthalmic formulations of levobunolol may contain sulfites. Patients with sulfite hypersensitivity may develop a local or systemic allergic reaction, including anaphylaxis. Asthmatic patients appear to be at higher risk than the general population for the development of this reaction. Levobunolol is contraindicated in patients exhibiting hypersensitivity to the drug or any of its excipients. Levobunolol is relatively contraindicated in hepatic impairment because of possible decreased clearance of the drug since it is principally metabolized by the liver. Dosage adjustment may be necessary in patients with hepatic disease. Levobunolol may produce a myasthenic condition which manifests as ptosis, weakness of limbs, and double vision; therefore levobunolol should be avoided in patients with myasthenia gravis. Patients receiving levobunolol before or during surgery involving general anesthetics that have negative inotropic effects (e.g., ether, cyclopropane, or trichlorethylene) should be monitored closely for signs of heart failure. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery in patients receiving beta-blockers. If discontinuation of the drug is indicated, therapy should be stopped 2 days prior to surgery. In general, beta-blockers can be used safely in elderly patients, however these patients may have unpredictable responses to systemic beta-blockade. Elderly patients appear to be more likely to experience adverse systemic effects following ophthalmic application of beta-blockers. Levobunolol is classified as a pregnancy category C drug by the FDA and appropriate consideration of risk/benefit of the use of the drug during pregnancy is prudent. Levobunolol is distributed into breast milk and should be used with caution in women breast-feeding their infants. Interactions Patients who are receiving systemic beta-blockers with ophthalmic beta-blockers should be observed for potential additive effects on intraocular pressure or excessive beta-blocking effects (see Adverse Effects). Due to the potential systemic absorption of ophthalmic beta-blockers, patients receiving concurrent oral or parenteral calcium-channel blockers (especially diltiazem or verapamil) or beta-blockers should be monitored for possible atrioventricular conduction disturbances, and/or left ventricular impairment. The concomitant use of ophthalmic beta-blockers in patients receiving antiarrhythmics which slow AV conduction (such as amiodarone, cardiac glycosides, diltiazem, and verapamil) may result in additive negative dromotropic effects, especially in patients with pre-existing cardiac disease or left ventricular dysfunction. Since ophthalmic levobunol may be systemically absorbed, there is potential for enhanced hypotensive effects when it is given with antihypertensive agents, including other beta-blockers. Hypotension can be potentiated when beta-blockers are coadministered with dihydroperidine calcium-channel blockers such as nifedipine. Close observation of the patient is recommended when a beta-blocker is administered to patients receiving catecholamine-depleting drugs such as reserpine, other rauwolfia alkaloids, or guanethidine, because of possible additive effects resulting in hypotension and/or bradycardia. Concurrent use of mefloquine and systemic beta-blockers has resulted in ECG abnormalities or cardiac arrest. Cevimeline may alter cardiac conduction and/or heart rate. Conduction disturbances are possible with concurrent use of beta-blockers and cevimeline. Use of topical epinephrine of dipivefrin as adjunctive therapy to further reduce IOP with levobunolol may result in mydriasis. Concurrent use of ophthalmic beta-blockers with sympathomimetics or psychostimulants such as amphetamine may result in antagonism of desired therapeutic effects of either therapeutic agent, although the primary interaction is more likely to be a decrease in the ophthalmic effects of the beta-blocker. Cimetidine interferes with the hepatic metabolism of levobunolol thereby causing reduced clearance of levobunolol and potentially increasing its pharmacodynamic effects. General anesthetics can potentiate the antihypertensive effects of beta-blockers and can produce prolonged hypotension. Patients receiving beta-blockers before or during surgery involving general anesthetics that possess negative inotropic effects (e.g., ether or cyclopropane) should be monitored closely for signs of heart failure. The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to major surgery is controversial. beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. Severe, protracted hypotension and difficulty in restarting the heart have been reported after surgery on patients receiving beta-blockers. For these reasons, in patients undergoing elective surgery, gradual withdrawal of ophthalmic beta-adrenergic receptor blocking agents may be appropriate, depending an evaluation of the potential risks and benefits. If systemic absorption of ophthalmic beta-blockers occurs, beta-blockade can mask the signs and symptoms of acute hypoglycemia during therapy with antidiabetic agents (e.g., tachycardia, palpitations, blood pressure changes, tremor, and anxiety). Non-selective beta-blockers are more likely to cause this interaction. Selective beta-blockers antagonize beta2-receptors less than nonselective agents and, as a result, may cause fewer problems with blood glucose regulation. However, all beta-blockers can mask the tachycardic response to hypoglycemia. Adverse Reactions Ocular irritation (burning or stinging) occurs in approximately 30% of patients using levobunolol, although the reaction is usually transient. Levobunolol has been shown to be absorbed systemically. Rare deaths have been reported in patients at high risk for cardiac or pulmonary complications secondary to treatment with beta-blockers. Although the adverse effects of levobunolol are generally mild and temporary, sinus bradycardia, and/or bronchospasm have been reported with the use of ophthalmic beta-blockers. Adverse reactions usually occur at the onset of therapy and diminish over time. Of all of the potential adverse effects due to systemic absorption of ophthalmic beta-blockers, the most frequent and/or likely may be CNS effects including dizziness, fatigue and depression. Other CNS related side effects include nightmares and hallucinations which tend to occur more frequently in elderly patients.
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Levobunolol Betagan� |