Beta-adrenergic Blocking Agents (Ophthalmic)

This monograph includes information on the following:

1) Betaxolol
2) Carteolol  
3) Levobetaxolol 
4) Levobunolol
5) Metipranolol  
6) Timolol

VA CLASSIFICATION
Primary: OP110

Commonly used brand name(s): AKBeta4; Apo-Timop6; Betagan4; Betaxon3; Betimol6; Betoptic1; Betoptic S1; Novo-Levobunolol4; Novo-Timol6; Ocupress2; Ophtho-Bunolol4; OptiPranolol5; Tim-AK6; Timoptic6; Timoptic in Ocudose6; Timoptic-XE6.

Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).

Not commercially available in Canada.



Category:


Antiglaucoma agent (ophthalmic)—

Indications

Note: Bracketed information in the Indications section refers to uses that are not included in U.S. product labeling.

Accepted

Glaucoma, open-angle (treatment) or
Hypertension, ocular (treatment)—Ophthalmic beta-adrenergic blocking agents are indicated in the treatment of chronic open-angle glaucoma . They also may be used in the treatment of ocular hypertension. {239}2 They may be used alone or in combination with other antiglaucoma agents. {239}1 {239}0 {236}9 {236}8 {236}7 {236}6 {236}5 {236}4 {236}3 {236}2 {236}1 {236}0 {236}9 {236}8 {236}7 {236}6 {236}5{236}4
—Ophthalmic beta-adrenergic blocking agents have been used as long-term ocular hypotensive therapy in glaucoma patients who have undergone laser trabeculectomy and in some cases of secondary glaucoma. They are well tolerated in aphakic glaucoma patients and in glaucoma patients who wear hard or soft contact lenses. {236}3 {236}2 {236}1 {236}0 {97} {98} {123} {150} {158} {166} {167} {173} {174} {175}

[Glaucoma, angle-closure (treatment adjunct)]—Betaxolol1, carteolol, levobetaxolol, levobunolol1 , metipranolol, and timolol may be used in conjunction with miotics to reduce intraocular pressure in acute and chronic angle-closure glaucoma. However, the ophthalmic beta-adrenergic blocking agent"s action alone is unlikely to terminate an acute attack of angle-closure glaucoma, because the agent produces little or no constriction of the pupil. Constriction of the pupil is necessary to pull the iris away from the trabeculum to relieve blockage of the trabecular meshwork. {09} {24} {52} {74} {158} {166} {167} {173} {174} {175}{250}

[Glaucoma, angle-closure, during or after iridectomy (treatment) ]1 or
[Glaucoma, malignant (treatment)]1—Ophthalmic beta-adrenergic blocking agents may be used to lower intraocular pressure in the treatment of angle-closure glaucoma during or after iridectomy and in the treatment of malignant glaucoma. {09} {90} {91} {122} {156} {207}

Note: Ophthalmic preparations of betaxolol and levobetaxolol may be especially useful in the treatment of glaucoma in patients with pulmonary disease because they are relatively {205} selective beta-1-adrenergic antagonists. {09} {45} {50} {51} {52}{250} Although ophthalmic betaxolol can have significant effects on pulmonary function in persons with pulmonary disease, it appears to do so much less frequently than nonselective beta-adrenergic antagonists. Ophthalmic levobetaxolol is expected to show a similar sparing of pulmonary function.{205}{250}

1 Not included in Canadian product labeling.



Pharmacology/Pharmacokinetics

Physicochemical characteristics:
Molecular weight—
    Betaxolol hydrochloride: 343.89 {167}
    Carteolol hydrochloride: 328.84 {158}
    Levobetaxolol hydrochloride: 343.89{250}
    Levobunolol: 327.85 {08}
    Metipranolol: 309.41 {141}
    Timolol maleate: 432.49 {08}


pH
    Metipranolol hydrochloride ophthalmic solution: 5 to 5.8 {174}
    Levobetaxolol hydrochloride ophthalmic suspension: 5.5 to 7.5 {250}

Mechanism of action/Effect:

Betaxolol and levobetaxolol are cardioselective (beta-1-adrenergic) receptor blocking agents{250} Carteolol, levobunolol, metipranolol, and timolol are beta-1 and beta-2 (nonselective) adrenergic blocking agents. The exact mechanism of the ocular hypotensive action of ophthalmic beta-adrenergic blocking agents has not been established. {03} {20} {34} {52} {86} {150} {158} {167} {173} {174} {175}{250} However, it appears that the ophthalmic beta-adrenergic blocking agents reduce aqueous humor production, {03} {54} {80} {162} {167} {173} {174} {175}{250} as demonstrated by tonography and fluorophotometry. {167} {175}{250} A slight increase in aqueous humor outflow may be an additional mechanism. {174} {175}


Other actions/effects:

Ophthalmic beta-adrenergic blocking agents, if systemically absorbed, are capable of producing beta-adrenergic receptor blockade in the bronchi and bronchioles. (This is less likely to occur with ophthalmic betaxolol or levobetaxolol because they are relatively selective beta-1-adrenergic blocking agents.) {162} {167} {205} {220}{250} This action results in an increase in airway resistance because of unopposed parasympathetic activity. {149} {158} {173} {174} {175} This effect is in keeping with the beta-2-adrenergic blocking action of these medications. {03} It is possible that carteolol, because of its partial beta-agonist activity, may have less of a beta-blockade effect {03} {158} {162} {163} than the other ophthalmic beta-2-adrenergic blocking agents; {162} {167} {173} {174} {175} however, the possible protection conferred by the beta-agonist effect has not been clinically evaluated. {162} {163} Betaxolol 1% solution, when compared to a placebo, was not shown to have a significant effect on pulmonary function as measured by forced expiratory volume in 1 second (FEV 1), forced vital capacity (FVC), and FEV 1/VC. {167} However, in clinical use, ophthalmic betaxolol has caused a worsening of respiratory symptoms in some patients with pulmonary disease. {205} {220}

Ophthalmic beta-adrenergic blocking agents, if systemically absorbed, are also capable of reducing heart rate, myocardial contractility, and cardiac output, resulting in bradycardia and hypotension, in both healthy individuals and patients with heart disease. This is in keeping with the beta-1-adrenergic blocking action of these medications. {03} {04} {158} {167} {173} {174} {175}

The ophthalmic beta-adrenergic blocking agents do not have significant membrane-stabilizing (local anesthetic) activity. {158} {162} {167} {173} {174} {175}{250}

Ophthalmic beta-adrenergic blocking agents reduce normal as well as elevated intraocular pressure (IOP), whether or not it is accompanied by glaucoma. {158} {167} {173} {174} {175}{250}

Ophthalmic beta-adrenergic blocking agents have little or no effect on pupil size or accommodation compared with miosis produced by cholinergic agents. {03} {158} {166} {173} {174} {175}{250}

Absorption:

Ophthalmic beta-adrenergic blocking agents may be systemically absorbed. {28} {41} {45} {158} {162} {167} {173} {174} {175}{250}

Half-life:

Levobetaxolol—Approximately 20 hours.{250}

Onset of action:

Betaxolol, levobetaxolol, metipranolol, and timolol—Within 30 minutes following a single dose. {03} {166} {167} {174} {175} {205}{250}

Levobunolol—Within 1 hour following a single dose. {173}

Peak serum concentration:

Timolol maleate ophthalmic solution—0.46 nanogram per mL following morning dosing and 0.35 nanogram per mL following afternoon dosing. {243}

Timolol maleate gel-forming ophthalmic solution—0.28 nanogram per mL following morning dosing. {236}

Time to peak effect:

Betaxolol, carteolol, levobetaxolol, and metipranolol—Approximately 2 hours following a single dose. {166} {167} {174} {200}{250} This applies to both betaxolol ophthalmic solution and suspension. {166} {167}

Levobunolol—Between 2 and 6 hours following a single dose. {173}

Timolol—Within 1 to 2 hours following a single dose. {175}

Duration of action:

Betaxolol and levobetaxolol—12 hours, following a single dose of either the ophthalmic solution or suspension. {07} {166} {167}{250}

Carteolol—More than 6 to 8 hours. {165} {200} {201} {202}

Levobunolol and timolol—A significant lowering of intraocular pressure may be maintained for up to 24 hours following a single dose. {03} {15} {25} {173} {175}

Metipranolol—A reduction in intraocular pressure can be demonstrated 24 hours following a single dose. {174} {205}


Precautions to Consider

Cross-sensitivity and/or related problems

Patients sensitive to any of the ophthalmic or systemic beta-adrenergic blocking agents, such as acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, levobetaxolol, levobunolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, or timolol, may be sensitive to any other beta-adrenergic blocking agent also. {173}

Patients sensitive to sulfites may be sensitive to levobunolol hydrochloride ophthalmic solution which contains sodium metabisulfite {173}.

Carcinogenicity

Betaxolol—In lifetime studies in mice and rats, betaxolol has not been shown to be carcinogenic when administered orally at doses of 6, 20, or 60 mg per kg of body weight (mg/kg) per day (mice) and at doses of 3, 12, or 48 mg/kg per day (rats). {166}

Carteolol—In 2-year studies in mice and rats, carteolol has not been shown to be carcinogenic when administered orally at doses of up to 40 mg/kg per day. {158}

Metipranolol—In lifetime studies, metipranolol has not been shown to be carcinogenic when administered orally to mice at doses of 5, 50, and 100 mg/kg per day and to rats at doses of up to 70 mg/kg per day. {174}

Timolol—In a lifetime study in mice, timolol increased the incidence of malignant pulmonary tumors and mammary adenocarcinomas in female mice when administered orally at doses of 500 mg/kg per day, but not at 5 or 50 mg/kg per day. {175}

Tumorigenicity

Betaxolol, carteolol, and levobetaxolol—Unknown.

Levobunolol—In a lifetime study, levobunolol increased the incidence of benign leiomyomas in female mice when administered orally at doses of 200 mg/kg per day (14,000 times the recommended human dose for glaucoma), but did not produce this effect at doses of 12 or 50 mg/kg per day (850 and 3500 times the human dose). In a 2-year study in rats, levobunolol increased the incidence of benign hepatomas in male rats when administered orally at doses 12,800 times the recommended human dose for glaucoma. Similar differences were not observed in rats when levobunolol was administered at oral doses equivalent to 350 to 2000 times the recommended human dose for glaucoma. {173}

Metipranolol—In lifetime studies, female mice had an increased number of pulmonary adenomas when they were given metipranolol at an oral dose of 5 mg/kg per day. However, doses of 50 and 100 mg/kg per day did not produce this effect. {174}

Timolol—In a 2-year study in rats, timolol increased the incidence of adrenal pheochromocytomas in male rats when administered orally at doses of 300 mg/kg per day (which are 250 times the maximum recommended human oral dose of 30 mg [1 drop of ophthalmic timolol contains about 1/150th of this dose or about 0.2 mg of timolol]). However, similar effects were not observed in rats when timolol was administered at oral doses equivalent to 20 or 80 times the maximum recommended human oral dose. In a lifetime study in mice, timolol increased the incidence of benign pulmonary tumors and benign uterine polyps in female mice when administered orally at doses of 500 mg/kg per day. However, doses of 5 and 50 mg/kg per day did not produce this effect. In addition, timolol increased the overall incidence of neoplasms in female mice at oral doses of 500 mg/kg per day. {175}

Mutagenicity

BetaxololIn vitro and in vivo bacterial and mammalian cell assays have not shown betaxolol to be mutagenic. {166}

Carteolol—Carteolol was not shown to be mutagenic in the Ames test and recombinant (rec)-assay and in the in vivo cytogenetic and dominant lethal assays. {158}

Levobetaxolol—Potential mutagenicity was shown in vitro in the Chinese Hamster Ovarian Cell sister chromatid exhange assay, in the presence of metabolic activation systems. {250}

Levobunolol—In microbiological and mammalian in vitro and in vivo assays, levobunolol was not shown to be mutagenic. {173}

Metipranolol—Metipranolol was nonmutagenic in in vivo and in vitro bacterial and mammalian cell assays. {174}

Timolol—Timolol was not shown to be mutagenic when tested in vivo (mouse) in the micronucleus test and cytogenetic assay (at doses up to 800 mg/kg) and in vitro in a neoplastic cell transformation assay (up to 0.1 mg per mL). {175}

Pregnancy/Reproduction
Fertility—
Betaxolol: Studies in rabbits and rats have shown that betaxolol, administered at oral doses above 12 mg/kg and 128 mg/kg, respectively, causes drug-related postimplantation loss. {166}

Carteolol: Studies in rats and mice have not shown that carteolol causes any adverse effects on male and female fertility when administered at doses of up to 150 mg/kg per day. {158}

Levobetaxolol:

Reproduction and fertility studies in rabbits showed evidence of drug related postimplantation loss at doses of levobetaxolol 12 mg/kg per day. {250}

Levobunolol: Reproduction and fertility studies in rats showed no adverse effects on male or female fertility when levobunolol was administered at doses of up to 1800 times the recommended human dose for glaucoma. {173}

Metipranolol: Reproduction and fertility studies on metipranolol in rats and mice showed no adverse effect on female or male fertility at oral doses of up to 25 mg/kg per day and 50 mg/kg per day, respectively. {174}

Timolol: Reproduction and fertility studies in rats have not shown that timolol causes any adverse effects on male and female fertility when administered at doses of up to 125 times the maximum recommended human oral dose. {175}

Pregnancy—

Betaxolol

Adequate and well-controlled studies in humans have not been done.

In animal studies, betaxolol was not shown to cause teratogenic effects or other adverse effects on reproduction at subtoxic doses. {166}

FDA Pregnancy Category C.



Carteolol

Adequate and well-controlled studies in humans have not been done. {158}

In rabbits and rats, carteolol, administered in doses approximately 1052 and 5264 times the maximum recommended human oral dose of 10 mg per 70 kg of body weight per day, respectively, resulted in maternotoxicity, increased incidence of fetal resorptions, and decreased fetal weights. {158} In rats, carteolol, administered in doses approximately 212 times the maximum recommended human oral dose, resulted in a dose-related increase in wavy ribs in the developing rat fetus. {158} However, in mice, carteolol, administered in doses up to approximately 1052 times the maximum recommended human oral dose, did not result in wavy ribs. {158}

FDA Pregnancy Category C.



Levobetaxolol

Adequate and well-controlled studies in humans have not been done. {250}

Sternebrae malformations were observed in rabbits administered levobetaxolol 4 mg/kg per day. {250}

FDA Pregnancy Category C.



Levobunolol

Adequate and well-controlled studies in humans have not been done.

Although levobunolol has been shown to cause fetotoxicity in rabbits when administered at doses equivalent to 200 and 700 times the recommended dose for the treatment of glaucoma, similar studies in rats have not shown levobunolol to cause fetotoxic effects when administered at doses of up to 1800 times the human dose for glaucoma. Moreover, in teratogenicity studies in rats, levobunolol was not shown to cause fetal malformations when administered at doses of up to 25 mg/kg per day (1800 times the recommended human dose for glaucoma). Also, levobunolol was not shown to have adverse effects on the postnatal development of animal offspring. {173}

FDA Pregnancy Category C.



Metipranolol

Adequate and well-controlled studies in humans have not been done. {174}

No metipranolol-related effects were reported for the segment II teratology study in fetal rats when metipranolol was administered orally to pregnant rats in doses of up to 50 mg/kg per day during organogenesis. {174} However, metipranolol has been shown to increase fetal resorption, fetal death, and delayed development when administered orally to pregnant rabbits at 50 mg/kg during organogenesis. {174}

FDA Pregnancy Category C.



Timolol

Although adequate and well-controlled studies in humans have not been done, timolol may be absorbed systemically.

Studies in rats have shown that timolol at doses of up to 50 mg/kg per day (50 times the maximum recommended human oral dose) causes delayed fetal ossification; however, there were no adverse effects on postnatal development of offspring. Teratogenic studies in mice and rabbits have not shown that timolol at doses of up to 50 mg/kg per day causes fetal malformations. In mice, timolol at doses of 1 gram per kg per day (1000 times the maximum recommended human oral dose) was maternotoxic and resulted in increased incidence of fetal resorptions. In rabbits, timolol at doses 100 times the maximum recommended human oral dose caused increased incidence of fetal resorptions but not maternotoxicity. {175}

FDA Pregnancy Category C.


Breast-feeding

Betaxolol—Systemic betaxolol is distributed into breast milk in large enough quantities to have pharmacological effects. {152} However, it is not known whether ophthalmic betaxolol is distributed into breast milk {166} {167} and problems in humans have not been documented.

Carteolol—It is not known whether systemic or ophthalmic carteolol is distributed into human breast milk; however, carteolol has been shown to be distributed into animal milk. {153} {158}

Levobetaxolol—It is not known whether ophthalmic levobetaxolol is distributed into human breast milk.{250}

Levobunolol—It is not known whether ophthalmic levobunolol is distributed into breast milk {173}. However, problems in humans have not been documented.

Metipranolol—It is not known whether ophthalmic metipranolol is distributed into breast milk. However, problems in humans have not been documented. {174}

Timolol—Systemic timolol is distributed into breast milk. {03} Problems in humans have not been documented for ophthalmic timolol; however, ophthalmic timolol may be systemically absorbed and distributed into the breast milk, possibly causing serious adverse reactions in the infants of nursing mothers. {03} {65} {66} {175}

Pediatrics

Although appropriate studies on the relationship of age to the effects of beta-adrenergic blocking agents, including the ophthalmic blocking agents, have not been performed in the pediatric population, infants should be treated cautiously and monitored for signs of dyspnea. In addition, the use of nasolacrimal occlusion should be emphasized for both infants and children. {03} {90} {92} {115} {121} {158} {174}


Geriatrics


Although appropriate studies on the relationship of age to the effects of ophthalmic beta-adrenergic blocking agents have not been performed in the geriatric population, no geriatrics-specific problems have been documented to date. However, if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, the same geriatrics-related problems may occur that are possible with the systemic beta-adrenergic blocking agents. These include bradycardia, {152} increased myocardial depression because of reduced metabolic and excretory capabilities in many elderly patients, and the increased risk of beta-adrenergic blocking agent–induced hypothermia in elderly patients. {47} {88} {89} {94} {107} {155} {232}

In addition, elderly patients are more likely to have age-related peripheral vascular disease, which may require caution in patients receiving beta-adrenergic blocking agents.

Surgical

Gradual withdrawal of ophthalmic beta-adrenergic blocking agent therapy may be advisable prior to general anesthesia because of the beta-adrenergic blocking agent–induced suppression of the cardiac response to beta-adrenergically mediated sympathetic reflex stimuli {166} {173}{250}.

Drug interactions and/or related problems
The following drug interactions and/or related problems have been selected on the basis of their potential clinical significance (possible mechanism in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):


Note: Combinations containing any of the following medications, depending on the amount present, may also interact with this medication.
Information concerning interactions between ophthalmic beta-adrenergic blocking agents and other medications is still limited. Some of the following potential interactions apply to beta-adrenergic blocking agents in general and are stated for cautionary reference until additional information specific to the ophthalmic beta-adrenergic blocking agents is available.

Allergen immunotherapy or
Allergenic extracts for skin testing    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use of these agents in patients using ophthalmic beta-adrenergic blocking agents may increase the potential for serious systemic reaction or anaphylaxis {17} {21} {33} {35} {208})


Amiodarone    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use may potentiate bradycardia, sinus arrest, and atrioventricular [AV] block, especially in patients with underlying sinus function impairment {189} {190} {191} {209})


Anesthetics, hydrocarbon inhalation, such as:
Chloroform
Cyclopropane
Enflurane
Halothane
Isoflurane
Methoxyflurane
Trichloroethylene     (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use of hydrocarbon inhalation anesthetics may increase the risk of myocardial depression and hypotension because the beta-adrenergic blockade reduces the ability of the heart to respond to beta-adrenergically mediated sympathetic reflex stimuli; if it is necessary to reverse the effects of beta-adrenergic blocking agents during surgery, agonists, such as dobutamine, dopamine, isoproterenol, or norepinephrine, may be used but should be administered with caution, especially in patients receiving halothane. Some clinicians recommend gradual withdrawal of beta-adrenergic blocking agents 48 hours prior to elective surgery; however, this recommendation is controversial {85} {151} {152} {153} {154} {158} {166} {167} {173} {174} {175} {224} {225})


Antidiabetic agents, oral or
Insulin    (systemic beta-adrenergic blocking agents may affect diabetes mellitus therapy. This may also occur with ophthalmic beta-adrenergic blocking agents if there is significant systemic absorption. Nonselective beta-adrenergic blocking agents impair glycogenolysis and the hyperglycemic response to endogenous epinephrine, leading to persistence of hypoglycemia. Also, beta-adrenergic blocking agents, especially nonselective agents, decrease the release of insulin in response to hyperglycemia. Dosage adjustment of the antidiabetic agent may be required to avoid a severe hypoglycemic reaction. In addition, beta-adrenergic blocking agents may complicate patient monitoring by masking symptoms of hypoglycemia caused by epinephrine, such as increased heart rate and increased blood pressure, but not dizziness and sweating. Although selective or relatively selective beta-adrenergic blocking agents usually cause fewer problems with blood glucose levels, they may still mask symptoms of hypoglycemia {58} {68} {121} {151} {152} {153} {154} {158} {166} {167} {173} {174} {175} {204} {226} {227} {228} {229} {230} {231}{250})


Beta-adrenergic blocking agents, systemic    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use of these medications may result in an additive effect on intraocular pressure or in additive systemic effects of beta-adrenergic blockade {152} {158} {167} {173} {174} {175}{250})


Calcium channel blocking agents    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use of calcium channel blocking agents, such as bepridil, diltiazem, flunarizine, isradipine, nicardipine, nifedipine, nimodipine, and verapamil, may result in atrioventricular conduction disturbances, left ventricular failure, and hypotension; in some patients, if a calcium antagonist is necessary, nicardipine or nifedipine may be preferred because they have less effect on heart rate and conduction, although they may also cause greater hypotension; concurrent use of calcium channel blockers and ophthalmic beta-adrenergic blocking agents should be used with care {121} in patients with impaired cardiac function {36} {69} {90} {121} {142} {152} {153} {154} {157} {174} {175})


Catecholamine-depleting medications, such as the rauwolfia alkaloids:
Alseroxylon
Deserpidine
Rauwolfia serpentina
Reserpine {152} {153} {158} {167} {173} {174} {175}{250}    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use of catecholamine-depleting medications may result in additive and possibly excessive beta-adrenergic blockade; although this effect is largely theoretical, close observation is recommended, since bradycardia and marked hypotension may occur {90} {151} {152} {153} {154} {158} {166} {167} {173} {174} {175}{250})


Cimetidine    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use with cimetidine may reduce the clearance of hepatically metabolized beta-adrenergic blocking agents, resulting in elevations of plasma concentrations {48} {49} {56} {57} {210})


Clonidine    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs during concurrent use, discontinuation of clonidine therapy may increase the risk of clonidine-withdrawal hypertensive crisis; ideally, beta-adrenergic blocking agents should be discontinued several days before clonidine is discontinued; blood pressure control may also be impaired when the two are combined {159} {172} {211})


Cocaine    (cocaine may inhibit the therapeutic effects of systemic beta-adrenergic blocking agents, and may also have this effect on ophthalmic beta-adrenergic blocking agents)

    (concurrent use of cocaine with systemic beta-adrenergic blocking agents may increase the risk of hypertension, excessive bradycardia, and possibly heart block because beta-adrenergic blockade may leave cocaine"s alpha-adrenergic activity unopposed. This may also occur with ophthalmic beta-adrenergic blocking agents if significant systemic absorption of the ophthalmic beta-adrenergic blocking agent occurs {83} {121} {161} {168} {169} {170})


Contrast media, iodinated    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use with intravenous contrast media may increase the risk of moderate to severe anaphylaxis; these reactions may be refractory to treatment. There was no consensus among USP experts as to whether or not this interaction was clinically significant {60} {62} {64} {212})


Fentanyl and derivatives    (preoperative chronic use of ophthalmic beta-adrenergic blocking agents [with the possible exception of betaxolol] may increase the risk of initial bradycardia following induction doses of fentanyl or any of its derivatives {90} {119} {120} {213})


Flecainide    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use may result in additive negative cardiac inotropic effects, especially, or perhaps only, in patients with cardiac problems {121} {124} {125} {126} {214})


Hypotension-producing medications, other (See Appendix II )    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents [with the possible exception of betaxolol and levobetaxolol] occurs, concurrent use may potentiate the hypotensive effects of these medications {90}{250})


Methacholine    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, methacholine inhalation challenge should not be performed, since the reaction to methacholine may be exaggerated or prolonged and may not respond as rapidly to treatment with bronchodilators {182} {183} {215})


Nicotine    (nicotine increases the metabolism of beta-adrenergic blocking agents; if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, patients undergoing smoking cessation may experience an increase in the frequency of side/adverse effects caused by the blocking agents because of the subsequent decrease in the blocking agents" metabolism. There was no consensus among USP experts as to whether or not this interaction was clinically significant {76} {184} {216})


Phenothiazines    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use may result in an increased plasma concentration of either the phenothiazine or the ophthalmic beta-adrenergic blocking agent because of inhibition of metabolism. This may result in additive hypotensive effects, irreversible retinopathy, cardiac arrhythmias, or tardive dyskinesia. There was no consensus among USP experts as to whether or not this interaction was clinically significant {130} {131} {132} {133} {217})


Phenytoin, intravenous    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use may cause additive cardiac depressant effects. There was no consensus among USP experts as to whether or not this interaction was clinically significant {192} {218})


Quinidine    (beta-adrenergic blocking effects of timolol may be potentiated because quinidine inhibits cytochrome P450 CYP2D6 {243})


Sympathomimetics, systemic    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, concurrent use may result in inhibition of the beta-adrenergic effects of sympathomimetics; depending on the type of sympathomimetic, this inhibition will occur with the beta-1-adrenergic cardiac effects and/or the beta-2-adrenergic bronchodilating effect; betaxolol and levobetaxolol will block primarily the beta-1-adrenergic effects)

    (concurrent use of norepinephrine may result in mutual inhibition of therapeutic effects {140} {145} {151} {158} {166} {167} {174} {193} {194} {195} {196} {197} {205} {221}{250})


Xanthines, such as:
Aminophylline
Caffeine
Dyphylline
Oxtriphylline
Theophylline    (if significant systemic absorption of ophthalmic beta-adrenergic blocking agents [with the possible exception of betaxolol] occurs, concurrent use may result in inhibition of therapeutic effects of xanthines; in addition, concurrent use of xanthines [except dyphylline] with the ophthalmic beta-adrenergic blocking agents [with the possible exception of betaxolol] may decrease theophylline clearance, especially in patients with increased theophylline clearance induced by smoking; concurrent use requires careful monitoring {90} {139})

    (concurrent use with caffeine may result in inhibition of caffeine"s therapeutic effect {134} {135} {136} {137} {219})


Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).


Except under special circumstances, this medication should not be used when the following medical problems exist:
» Asthma, bronchial (or history of) or {148} {158} {174}
» Pulmonary disease, obstructive, severe chronic {158} {174}    (severe respiratory reactions, including death due to bronchospasm, have been reported in patients with asthma, following administration of the ophthalmic beta-adrenergic blocking agents. {38} {61} {78} {79} {95} {102} {158} {174}{250} Although betaxolol (and, possibly, levobetaxolol)appears to have a minimal effect on pulmonary function, {166} {167} {205} caution should be used in patients with severe restriction of pulmonary function {166} {167}{250})


» Cardiac failure, overt or {158} {166} {174}{250}
» Cardiogenic shock or {158} {166} {174}{250}
» Heart block, 2nd- or 3rd-degree atrioventricular (AV) or {158} {166} {174}{250}
» Sinus bradycardia {158} {166} {174}{250}    (risk of further myocardial depression may occur with the use of the ophthalmic beta-adrenergic blocking agents {61} {87} {167})


» Previous allergic reaction to the ophthalmic beta-adrenergic blocking agent prescribed
Risk-benefit should be considered when the following medical problems exist
» Allergic reactions, severe, history of    (risk of developing unresponsiveness to usual doses of epinephrine used to treat anaphylactic reactions {166} {173}{250})


» Bronchitis, nonallergenic or chronic or {158} {174}
» Emphysema or {158} {174}
» Pulmonary function impairment, other {174}    (use of the ophthalmic beta-adrenergic blocking agents may promote bronchospasm and block bronchodilation produced by endogenous and exogenous catecholamine stimulation of beta-2-receptors. {27} {42} {158} {174}{250} Although the effects of betaxolol on pulmonary function have been shown in some studies to be minimal in patients with reactive airway disease, there have been reports of asthmatic attacks and pulmonary distress during betaxolol treatment {166} {167} {205} {220})


Cerebrovascular insufficiency {158} {174}    (potential effects on blood pressure and pulse; if signs of reduced cerebral blood flow occur following initiation of therapy, alternative therapy should be considered {39} {44} {158} {174} {175})


» Congestive heart failure    (risk of further depression of myocardial contractility {158} {173} {175}{250})


» Cardiac failure, history of or
Heart block, history of    (possible risk of myocardial depression; treatment should be discontinued at first signs of cardiac failure {31} {32} {166} {174}{250})


» Diabetes mellitus, especially labile diabetes or
» Hypoglycemia    (ophthalmic beta-adrenergic blocking agents may mask some signs and symptoms of hypoglycemia,{250} such as tachycardia and tremor, although they do not mask dizziness and sweating {04} {114} {158} {167} {174})


» Hyperthyroidism    (ophthalmic beta-adrenergic blocking agents may mask certain signs and symptoms of hyperthyroidism; abrupt withdrawal may precipitate a thyroid storm {03} {158} {167} {174}{250})


Myasthenia gravis    (beta-adrenergic blockade may potentiate muscle weakness related to certain myasthenic symptoms, such as diplopia, ptosis, and generalized weakness {29} {67} {108} {112} {158} {167} {174}{250})



Patient monitoring
The following may be especially important in patient monitoring (other tests may be warranted in some patients, depending on condition; » = major clinical significance):

Intraocular pressure determination    (recommended during, and following, the first month of therapy during which stabilization of the pressure-lowering response to the ophthalmic beta-adrenergic blocking agent usually occurs; thereafter, intraocular pressure should be determined as necessary {20} {91} {166} {167} {173} {175}{250})




Side/Adverse Effects

Note: Even in patients without a history of cardiac failure, continued depression of the myocardium with beta-blockers, {26} {158} {173} {175} including ophthalmic beta-adrenergic blocking agents, over a period of time can lead to cardiac failure, if significant systemic absorption occurs. {158} {173} {175} However, betaxolol, levobetaxolol, and metipranolol may be less likely to cause myocardial depression. {166} {174}{250} At the first sign or symptom of cardiac failure, the ophthalmic beta-adrenergic blocking agent should be discontinued. {158} {167} {173} {174} {175} {232} {250}
Although ophthalmic beta-adrenergic blocking agents have minimal membrane-stabilizing (local anesthetic) action, {26} {158} {162} {167} {173} {174} {175} {250}decreased corneal sensitivity may occur following prolonged use, and has been reported rarely with the use of betaxolol, levobunolol, and timolol, {166} {167} {173} {174} {175} but not with the use of metipranolol. {174} In contrast, carteolol has been reported to occasionally cause increased corneal sensitivity. {158}
Because of the relative selectivity of betaxolol and levobetaxolol for beta-1-adrenergic receptor inhibition, {52}{250}betaxolol and levobetaxolol may have less potential for systemic side/adverse effects than have the other ophthalmic beta-adrenergic blocking agents, which are nonselective beta-1 and beta-2 adrenergic receptor inhibitors. {45} {51} This may be especially important for patients for whom beta-2 adrenergic blockade could be harmful. {51}
The ophthalmic suspension dosage form of betaxolol appears to be less irritating to the eye than the ophthalmic solution dosage form, although eye irritation occurs more frequently than other side effects with both dosage forms.
The side effects listed below have been reported for one or more of the ophthalmic beta-adrenergic blocking agents. However, all of these side effects are possible with any of the ophthalmic beta-adrenergic blocking agents. In addition, since the ophthalmic beta-adrenergic blocking agents may be systemically absorbed, any of the side effects that are possible for the systemic beta-adrenergic blocking agents are also theoretically possible for the ophthalmic beta-adrenergic blocking agents.
A slight reduction in resting heart rate has been observed in patients receiving ophthalmic timolol maleate. {236} {243}


In patients receiving timolol maleate ophthalmic solution, a mean reduction of 2.9 beats per minute with a standard deviation of 10.2 was observed. {243}


In patients receiving the gel-forming ophthalmic solution of timolol maleate, a mean reduction of 0.8 beat per minute at twenty-four hours postdose and 3.8 beats per minute at two hours postdose was observed. {236}

The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:

Those indicating need for medical attention
Incidence more frequent
    
Conjunctival hyperemia (redness of eyes or inside of eyelids)—reported for carteolol, frequency 25% {158}

Incidence less frequent or rare
    
Anisocoria (different size pupils of the eyes)—reported for betaxolol {166}
    
blepharitis {59} {74} {174} {175} (irritation or inflammation of eyelid {81})—reported for metipranolol and timolol
    
blepharoconjunctivitis {158} {173} (irritation or inflammation of eye and eyelid {81})—reported for carteolol and levobunolol
    
cataracts {250} (blurred or decreased vision)—reported for levobetaxolol only
    
conjunctivitis {59} {74} {174} {175} (irritation or inflammation of eye {81})—reported for metipranolol and timolol
    
corneal punctate keratitis {167} (irritation or inflammation of eye {81})—reported for betaxolol
    
dermatitis of eyelid {174} ( irritation or inflammation of eyelid {81})—reported for metipranolol
    
edema {158} {174} (swelling of eye or eyelid {81})— reported for carteolol and metipranolol
    
iridocyclitis {173} (irritation or inflammation of eye {81})—reported for levobunolol
    
keratitis {59} {74} {166} {175} (irritation or inflammation of eye {81})—reported for betaxolol and timolol
    
blepharoptosis ( droopy upper eyelid)—reported for carteolol and timolol {109} {158} {175}
    
corneal staining (discoloration of the eyeball)—reported for betaxolol and carteolol {158} {166}
    
decreased corneal sensitivity —reported for betaxolol, levobunolol, and timolol {166} {173} {175}
    
diplopia (seeing double)—reported for timolol {175}
    
eye pain —reported for betaxolol suspension {167}
    
glossitis (redness or irritation of the tongue)—reported for betaxolol {167}
    
vision disturbances (blurred vision or other change in vision)—reported for betaxolol suspension, carteolol, metipranolol, and timolol {74} {150} {158} {167} {174} {175}
    
vitreous disorders —reported for levobetaxolol only {250}

Symptoms of systemic absorption
    
Allergic reaction (skin rash, hives, or itching)—reported for all except levobunolol {100} {166} {167} {173} {174} {175}
    
alopecia (hair loss)—reported for betaxolol , levobetaxolol, and timolol {138} {167} {175}{250}
    
anxiety or nervousness —reported for levobetaxolol andmetipranolol{174}{250}
    
arthritis or myalgia (muscle or joint aches or pain)— reported for levobetaxolol and metipranolol{147} {174}{250}
    
ataxia (clumsiness or unsteadiness)—reported for levobunolol only {173}
    
breast abscess {250}(breast pain)—reported for levobetaxolol only
    
change in taste —reported for carteolol and levobetaxolol{158}{250}
    
chest pain —reported for timolol only {175}
    
confusion or mental depression — reported for betaxolol, metipranolol, and timolol {12} {93} {110} {166} {167} {174} {175}
    
congestive heart failure (swelling of feet, ankles, or lower legs)—reported for betaxolol and timolol {12} {13} {16} {167} {175}
    
coughing, wheezing, or troubled breathing, especially in patients with predisposition to bronchoconstriction —reported for all {30} {53} {143} {148} {158} {162} {166} {167} {174} {175}{250}
    
cystitis {250}(bloody or cloudy urine ; difficult, burning, or painful urination)—reported for levobetaxolol only
    
diarrhea —reported for timolol only {12} {59} {175}
    
dizziness or feeling faint —reported for all {158} {167} {173} {174} {175}{250}
    
drowsiness —reported for metipranolol and timolol {12} {174}
    
ear pain {250}—reported for levobetaxolol only
    
epistaxis ( bleeding nose)— reported for metipranolol and timolol {03} {59} {174}
    
gout {250}(ankle, knee, or great toe joint pain; ankle, knee, or great toe joint swelling; lower back or side pain)—reported for levobetaxolol only
    
hallucinations —reported for timolol only {11} {12} {82} {175}
    
headache —reported for all {158} {166} {167} {173} {174} {175}{250}
    
heartblock —reported for betaxolol, levobetaxolol, and timolol {167} {175} {250}
    
hypercholesterolemia —reported for levobetaxolol only {250}
    
hyperlipidemia — reported for levobetaxolol only{250}
    
hypertension —reported for levobetaxolol, metipranolol, and timolol {03} {59} {174}{250}
    
hypertonia (muscle tightness or stiffness)— reported for levobetaxolol only{250}
    
hypotension (confusion; faintness; light-headedness)— reported for levobetaxolol only{250}
    
impotence (decreased sexual ability )—reported for timolol only {12} {55} {63} {93} {175} {181}
    
infection {250}(chills; fever)—reported for levobetaxolol only
    
insomnia ( trouble in sleeping)—reported for betaxolol and carteolol {158} {166} {167}
    
irregular, slow, or pounding heartbeat —reported for all {30} {53} {105} {113} {148} {158} {166} {167} {173} {174} {175}{250}
    
nasal congestion (stuffy nose)—reported for timolol only {175}
    
nausea or vomiting —reported for metipranolol and timolol {12} {174} {175}
    
otitis media {250}(earache; ringing or buzzing in ears)—reported for levobetaxolol only
    
paresthesia (burning or prickling feeling on body)— reported for timolol only {175}
    
pharyngitis (dryness or soreness of throat; hoarseness)—reported for levobetaxolol only {250}
    
psoriasis {250}(red, scaling, or crusted skin)— reported for levobetaxolol only
    
rhinitis or sinusitis (runny nose)—reported for carteolol, levobetaxolol, metipranolol, and timolol {106} {158} {174}{250}
    
systemic lupus erythematosus — reported for timolol only {01} {104}
    
tachycardia (fast, pounding, or irregular heartbeat)—reported for levobetaxolol only{250}
    
tinnitus {243} (ringing in the ears)— reported for levobetaxolol and timolol{250}
    
toxic epidermal necrolysis (raw or red areas of the skin)—reported for betaxolol only {166} {167}
    
unusual tiredness or weakness — reported for all {158} {167} {173} {174} {175}
    
vascular anomoly — reported for levobetaxolol only{250}
    
vertigo (dizziness; feeling of constant movement of self or surroundings)— reported for levobetaxolol only{250}



Those indicating need for medical attention only if they continue or are bothersome
Incidence more frequent
    
Blurred vision, transient —reported for levobetaxolol{250} and the timolol maleate gel-forming solution; usually lasts from thirty seconds to five minutes {236}
    
decreased night vision —reported for carteolol {158}
    
stinging of eye or other eye irritation, transient upon administration of medication —reported for betaxolol, levobetaxolol, levobunolol, and metipranolol {30} {52} {146} {150} {162} {167} {173} {174}{250}

Incidence less frequent or rare
    
Browache —reported with carteolol and metipranolol {174}
    
constipation —reported for levobetaxolol only{250}
    
corneal sensitivity —reported for carteolol {158}
    
crusting of eyelashes —reported with betaxolol suspension {167}
    
dermatitis {250}(blistering, crusting, irritation, itching, or reddening of skin; dry, scaly skin)—reported for levobetaxolol only
    
dryness of eye —reported with betaxolol suspension and timolol {167} {243}
    
dyspepsia {250}(acid or sour stomach; belching; heartburn; indigestion)— reported for levobetaxolol only
    
foreign body sensation {166} {167} (feeling of having something in the eye)—reported with betaxolol
    
increased sensitivity of eye to light —reported for betaxolol, carteolol, and metipranolol {150} {158} {166} {167} {174}
    
redness, itching, stinging, burning, or watering of eye or other eye irritation —reported for all; more frequent for carteolol and levobunolol {30} {74} {158} {166} {167} {173} {174} {175}
    
tendinitis {250}(inflammation, pain, or swelling in muscles)—reported for levobetaxolol only





Overdose
For specific information on the agents used in the management of ophthalmic beta-adrenergic blocking agents overdose, see:
   • Aminophylline in Bronchodilators, Theophylline-derivative (Systemic) monograph;
   • Atropine in Anticholinergics/Antispasmodics (Systemic) monograph;
   • Charcoal, Activated (Oral-Local) monograph;
   • Digitalis Glycosides (Systemic) monograph;
   • Dobutamine in Sympathomimetic Agents-Cardiovascular Use (Parenteral-Systemic) monograph;
   • Dopamine in Sympathomimetic Agents-Cardiovascular Use (Parenteral-Systemic) monograph;
   • Glucagon (Systemic) monograph;
   • Isoproterenol in Sympathomimetic Agents-Cardiovascular Use (Parenteral-Systemic) monograph;
   • Norepinephrine in Sympathomimetic Agents-Cardiovascular Use (Parenteral-Systemic) monograph; and/or
   • Theophylline in Bronchodilators, Theophylline-derivative (Systemic) monograph.
For more information on the management of overdose or unintentional ingestion, contact a Poison Control Center (see Poison Control Center Listing ).

Treatment of overdose
If an ophthalmic overdose occurs, immediately flush the eyes with warm tap water.

If an ophthalmic beta-adrenergic blocking agent is accidentally ingested, activated charcoal or gastric lavage may be appropriate to decrease further absorption. {06} {07}

For symptoms of systemic toxicity, the medication should be discontinued. Depending on severity of toxicity, the following supportive and symptomatic treatments should be utilized if necessary:


For bradycardia: Atropine (0.25 to 2 mg) should be administered intravenously to induce vagal blockade. If bradycardia persists, intravenous isoproterenol hydrochloride may be administered with caution. A transvenous cardiac pacemaker may be used, if necessary. {02} {03} {06} {07} {174}


For hypotension: Glucagon and sympathomimetic pressor agents, such as dobutamine, dopamine, or norepinephrine, may be used. (See Drug interactions and/or related problems for precautions in use of sympathomimetic vasopressors.) {02} {06} {174}


For bronchospasm: Isoproterenol hydrochloride should be administered. Additional therapy with a beta-2-agonist or a theophylline derivative may be used, if necessary. {06} {19}


For cardiac failure, acute: Digitalis, diuretics, and oxygen should be administered immediately. Intravenous aminophylline may be used in refractory cases. Also, glucagon hydrochloride may be used, if necessary. {174}


For heart block, second or third degree: Isoproterenol hydrochloride or a transvenous cardiac pacemaker should be used. {07}


Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Beta-adrenergic Blocking Agents (Ophthalmic).

In providing consultation, consider emphasizing the following selected information (» = major clinical significance):

Before using this medication
»   Conditions affecting use, especially:
Allergy to any of the beta-adrenergic blocking agents, either ophthalmic or systemic, such as acebutolol, atenolol, betaxolol, bisoprolol, carteolol, labetalol, levobetaxolol, levobunolol, metipranolol, metoprolol, nadolol, oxprenolol, penbutolol, pindolol, propranolol, sotalol, or timolol

Pregnancy—Ophthalmic beta-adrenergic blocking agents may be absorbed into the body. Studies in animals have not shown that betaxolol, levobunolol, metipranolol, or timolol causes birth defects. However, very large doses of carteolol given by mouth to pregnant rats have been shown to cause wavy ribs in rat babies. In addition, some studies in animals have shown that beta-adrenergic blocking agents increase the chance of death in the animal fetus





Use in children—Infants may be especially sensitive to the effects of ophthalmic beta-adrenergic blocking agents, thus increasing the risk of side effects






Use in the elderly—If significant systemic absorption of ophthalmic beta-adrenergic blocking agents occurs, the chance of side effects during treatment may be increased, since elderly people are especially sensitive to the effects of these medications
Other medical problems, especially bronchial asthma, or history of, severe chronic obstructive pulmonary disease, overt cardiac failure, 2nd- or 3rd-degree atrioventricular (AV) heart block, cardiogenic shock, sinus bradycardia, history of severe allergic reactions, nonallergenic or chronic bronchitis, emphysema or other pulmonary function impairment, congestive heart failure, history of cardiac failure, diabetes mellitus, spontaneous hypoglycemia, or hyperthyroidism

Proper use of this medication
» Proper administration technique; using nasolacrimal occlusion is especially important in infants and children

Preventing contamination: Not touching applicator tip to any surface; keeping container tightly closed

Proper use of levobunolol having compliance cap {173}

Proper use of gel-forming timolol solution

» Importance of not using more medication than the amount prescribed

Importance of removing soft contact lenses prior to administration for products containing benzalkonium chloride as a preservative {174} {236} {243}

» Proper dosing
Missed dose: If dosing schedule is—

• Once a day: Applying as soon as possible; not applying if not remembered until next day; applying regularly scheduled dose


• More than once a day: Applying as soon as possible; not applying if almost time for next dose; applying next dose at regularly scheduled time


» Proper storage

Precautions while using this medication
Regular visits to physician to check eye pressure during therapy

Checking with physician immediately if having ocular surgery, if trauma to the eye occurs, or an eye infection develops to determine if the present multidose container should continue to be used {236} {243}

Caution when driving or using machinery because of possible blurred vision {236}

» Caution if any kind of surgery (including dental surgery) or emergency treatment is required

» Diabetic patients: May mask some signs of hypoglycemia, such as increased pulse rate and trembling, but not dizziness and sweating; also, may cause decreased or sometimes increased blood glucose concentrations

Possible photophobia: Wearing sunglasses and avoiding too much exposure to bright light


Side/adverse effects
Signs of potential side effects, especially conjunctival hyperemia, anisocoria, blepharitis, blepharoconjunctivitis, cataracts, conjunctivitis, corneal punctate keratitis, dermatitis of eyelid, edema, iridocyclitis, keratitis, blepharoptosis, corneal staining, decreased corneal sensitivity, diplopia, eye pain, glossitis, vision disturbances, vitreous disorders, or symptoms of systemic absorption


General Dosing Information
Although some manufacturers recommend a dose of 2 drops of an ophthalmic solution at appropriate intervals, the conjunctival sac will usually hold 1 drop or less. {203} {205} {222} {223}

When one ophthalmic beta-adrenergic blocking agent is used to replace another, the original beta-blocker may {205} be discontinued simultaneously with initiation of therapy with the new one. {156} {175}

When an ophthalmic beta-adrenergic blocking agent is used to replace a single antiglaucoma agent other than another beta-blocker, the other antiglaucoma agent may be continued on the first day that the new beta-blocker is used but can {205} be discontinued on the second day. {52} {156} {166} {175}

When an ophthalmic beta-adrenergic blocking agent is used to replace several concomitantly administered antiglaucoma agents, the patient"s dosage should be individualized as required. If any of the other antiglaucoma agents used is a beta-blocker, it can {205} be discontinued before the new ophthalmic beta-adrenergic blocking agent is added to the regimen. The other antiglaucoma agents being used may be continued on the first day that the new beta-blocker is used but one of the agents should be discontinued on the second day. Then the remaining antiglaucoma agents may be decreased or discontinued according to the patient"s response. Additional adjustments usually should involve only one agent at a time and should be made at intervals of not less than one week. {52} {74} {156} {166} {175}

Ophthalmic beta-adrenergic blocking agents may be used concurrently with direct and indirect cholinergic agonists (e.g., pilocarpine, echothiophate, carbachol), beta-agonists (e.g., ophthalmic epinephrine or dipivefrin), or systemic carbonic anhydrase inhibitors (such as acetazolamide), if necessary to control intraocular pressure. {02} {22} {24} {43} {46} {52} {70} {71} {72} {74} {75} {90} {101} {158} {162} {166} {167} {173} {174} {175} {193} {195} {196} {197} {198}

In patients scheduled for major surgery, some practitioners recommend that beta-adrenergic blocking agents be gradually withdrawn 48 hours prior to surgery because beta-adrenergic receptor blockade impairs the ability of the heart to respond to beta-adrenergically mediated reflex stimuli. This recommendation is controversial. {03} However, since ophthalmic beta-adrenergic blocking agents may be absorbed systemically, gradual withdrawal of the medication should be considered for patients undergoing elective surgery because prolonged severe hypotension during anesthesia has occurred in some patients receiving systemic beta-adrenergic blocking agents. If necessary during surgery, the effects of beta-adrenergic blocking agents may be reversed by sufficient doses of agonists, such as isoproterenol, dopamine, dobutamine, or norepinephrine. {158} {166} {173} {174} {175}

To help reduce systemic side effects, the patient can {205} be instructed to close the eyes gently and apply pressure to the inner canthus of each eye in order to block lacrimal drainage through the tear ducts after instillation of the ophthalmic drops. {03} {07} {103} {111} {116} {199}

Products containing benzalkonium chloride as a preservative may be absorbed by soft contact lenses. Contact lenses should be removed prior to the administration of benzalkonium chloride–containing products. Lenses may be reinserted fifteen minutes after administration. {174} {236} {243}

BETAXOLOL

Summary of Differences


Indications:
Betaxolol may be especially useful in the treatment of glaucoma in patients with pulmonary disease.



Pharmacology/pharmacokinetics:
Mechanism of action/effect—Betaxolol is a cardioselective (beta-1-adrenergic) receptor blocking agent.

Other actions/effects—Betaxolol is less likely to {205} produce significant beta-adrenergic receptor blockade in the bronchi and bronchioles.

Duration of action—12 hours.



Fertility:
Studies in rabbits and rats have shown that betaxolol, at oral doses above 12 mg/kg and 128 mg/kg, respectively, causes drug-related postimplantation loss.



Breast-feeding:
Systemic betaxolol is distributed into breast milk in large enough quantities to have pharmacological effects. However, it is not known whether ophthalmic betaxolol is distributed into breast milk and problems in humans have not been documented.



Ophthalmic Dosage Forms

BETAXOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION USP

Note: The dosing and strength usually available are expressed in terms of betaxolol base.


Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.5% solution of betaxolol (base) two times a day. {84} {166}


Usual pediatric dose
Safety and efficacy have not been established. {166}

Strength(s) usually available
U.S.—


0.5% (5 mg base; 5.6 mg as hydrochloride) (Rx) [Betoptic{166} (benzalkonium chloride 0.01%) (edetate disodium) (sodium chloride) ( hydrochloric acid) (sodium hydroxide)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {166} in a tight container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


BETAXOLOL HYDROCHLORIDE OPHTHALMIC SUSPENSION

Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.25% suspension of betaxolol (base) two times a day. {84} {167}


Usual pediatric dose
Safety and efficacy have not been established. {167}

Strength(s) usually available
U.S.—


0.25% (2.5 mg base; 2.8 mg as hydrochloride) (Rx) [Betoptic S{167} (benzalkonium chloride 0.01%) (mannitol ) (poly(styrene-divinyl benzene) sulfonic acid) (Carbomer 934P) (edetate disodium) (hydrochloric acid) (sodium hydroxide )]

Canada—


0.25% (2.5 mg base; 2.8 mg as hydrochloride) (Rx) [Betoptic S{233} (benzalkonium chloride) (mannitol) (poly(styrene-divinyl benzene) sulfonic acid) ( carbomer 934P) (edetate disodium) (hydrochloric acid and/or sodium hydroxide)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {167} in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • Shake well. {167}
   • For the eye.
   • Keep container tightly closed.


CARTEOLOL

Summary of Differences


Pharmacology/pharmacokinetics:
Other actions/effects—Carteolol has intrinsic sympathomimetic activity. {158}

Duration of action—More than 6 to 8 hours.



Pregnancy:
In rabbits and rats, carteolol, administered in doses approximately 1052 and 5264 times the maximum recommended human oral dose of 10 mg per 70 kg of body weight per day, respectively, resulted in maternotoxicity, increased incidence of fetal resorptions, and decreased fetal weights. In rats, carteolol, administered in doses approximately 212 times the maximum recommended human oral dose, resulted in a dose-related increase in wavy ribs in the developing rat fetus. However, in mice, carteolol, administered in doses up to approximately 1052 times the maximum recommended human oral dose, did not result in wavy ribs.



Breast-feeding:
It is not known whether systemic or ophthalmic carteolol is distributed into human breast milk; however, carteolol has been shown to be distributed into animal milk.



Ophthalmic Dosage Forms

CARTEOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION

Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop two times a day. {158}


Usual pediatric dose
Safety and efficacy have not been established. {158}

Strength(s) usually available
U.S.—


1% (10 mg carteolol hydrochloride per mL) (Rx) [Ocupress{158} (benzalkonium chloride 0.005%) (sodium chloride) (monobasic sodium phosphate) (dibasic sodium phosphate)]

Canada—
Not commercially available.

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F), {158} in a well-closed container, unless otherwise specified by manufacturer. Protect from light. {158} Protect from freezing.

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


LEVOBETAXOLOL

Summary of Differences


Indications:
Levobetaxolol is expected to be effective for the treatment of glaucoma in patients with pulmonary reactive airway disease.



Pharmacology/pharmacokinetics:
Mechanism of action/effect—Levobetaxolol is a cardioselective (beta-1-adrenergic) receptor blocking agent.

Levobetaxolol is expected to produce less beta-adrenergic receptor blockade in the bronchi and bronchioles{250}.

Onset of action—30 minutes.

Duration of action—12 hours.

Time to peak effect—2 hours.



Fertility:
Post-implantation loss was observed in rabbits given oral levobetaxolol in doses of 12 mg/kg per day.



Pregnancy:
Sternebrae malformations were observed in rabbits given oral levobetaxolol in doses of 4 mg/kg per day.



Breast feeding:
It is not known whether ophthalmic levobetaxolol is distributed into human breast milk.



Ophthalmic Dosage Forms

LEVOBETAXOLOL HYDROCHLORIDE OPHTHALMIC SUSPENSION

Note: The dosing and strength usually available are expressed in terms of levobetaxolol base.


Usual adult dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.5% suspension of levobetaxolol (base) two times a day{250}.


Usual pediatric dose
Safety and efficacy have not been established{250}.

Usual geriatric dose
See Usual adult dose.

Strength(s) usually available
U.S.—


0.5% (5 mg base; 5.6 mg as hydrochloride (Rx) [Betaxon (benzalkonium chloride 0.01%) (mannitol) (poly(styrene-divinyl benzene) sulfonic acid) (Carbomer 974P) (boric acid) (N-lauroylsarcosine) (edetate disodium) (hydrochloric acid or tromethamine [to adjust pH]) (purified water ){250}]

Canada—
Not commercially available.

Packaging and storage:
Store upright between 4 and 25 °C (39 and 77 °F).{250} Protect from light.{250}

Auxiliary labeling:
   • For the eye.
   • Protect from light.
   • Shake well before using.


LEVOBUNOLOL

Summary of Differences


Pharmacology/pharmacokinetics:
Onset of action—Within 1 hour.

Time to peak effect—Between 2 and 6 hours.

Duration of action—Up to 24 hours.



Pregnancy:
Although levobunolol has been shown to cause fetotoxicity in rabbits when administered at doses equivalent to 200 and 700 times the recommended dose for the treatment of glaucoma, similar studies in rats have not shown levobunolol to cause fetotoxic effects when administered at doses of up to 1800 times the human dose for glaucoma. Moreover, in teratogenicity studies in rats, levobunolol was not shown to cause fetal malformations when administered at doses of up to 25 mg/kg per day (1800 times the recommended human dose for glaucoma). Also, levobunolol was not shown to have adverse effects on the postnatal development of animal offspring.



Ophthalmic Dosage Forms

LEVOBUNOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION USP

Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.25% solution two times a day or 1 drop of a 0.5% solution once a day. {18} {173}

Note: In patients with more severe or uncontrolled glaucoma, the 0.5% solution may be administered two times a day {173}.



Usual adult prescribing limits
Dosages above 1 drop of a 0.5% solution two times a day are generally not more effective. {173}

Usual pediatric dose
Safety and efficacy have not been established. {173}

Strength(s) usually available
U.S.—


0.25% (Rx) [AKBeta{234}] [Betagan{173} ( polyvinyl alcohol 1.4%) (benzalkonium chloride 0.004% ) (sodium metabisulfite) ( edetate disodium) (dibasic sodium phosphate) (monobasic potassium phosphate) (sodium chloride) (hydrochloric acid) ( sodium hydroxide)][Generic]{235}


0.5% (Rx) [AKBeta{234}] [Betagan{173} ( polyvinyl alcohol 1.4%) (benzalkonium chloride 0.004% ) (sodium metabisulfite) ( edetate disodium) (dibasic sodium phosphate) (monobasic potassium phosphate) (sodium chloride) (hydrochloric acid) ( sodium hydroxide)][Generic]{235}

Canada—


0.25% (Rx) [Betagan{245} (polyvinyl alcohol ) (benzalkonium chloride 0.004%) ( sodium metabisulfite) (edetate disodium) (dibasic sodium phosphate) (monobasic potassium phosphate) (sodium chloride) (hydrochloric acid and/or sodium hydroxide)] [Novo-Levobunolol{246}] [Ophtho-Bunolol{247} ( benzalkonium chloride 0.004%) (edetate disodium ) (polyvinyl alcohol) ( monobasic potassium phosphate) (sodium chloride ) (sodium metabisulfite) ( dibasic sodium phosphate) (sodium hydroxide or hydrochloric acid)]


0.5% (Rx) [Betagan{245} (polyvinyl alcohol ) (benzalkonium chloride 0.004%) ( sodium metabisulfite) (edetate disodium) (dibasic sodium phosphate) (monobasic potassium phosphate) (sodium chloride) (hydrochloric acid) (sodium hydroxide )] [Novo-Levobunolol{246}] [Ophtho-Bunolol{247} (benzalkonium chloride 0.004%) (edetate disodium) (polyvinyl alcohol) ( monobasic potassium phosphate) (sodium chloride ) (sodium metabisulfite) ( dibasic sodium phosphate) (sodium hydroxide or hydrochloric acid)]

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), in a tight container, unless otherwise specified by manufacturer. Protect from light. {173} Protect from freezing.

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


METIPRANOLOL

Summary of Differences
Pharmacology/pharmacokinetics: Duration of action—More than 24 hours.

Pregnancy: No metipranolol-related effects were reported for the segment II teratology study in fetal rats when metipranolol was administered orally to pregnant rats in doses of up to 50 mg/kg per day during organogenesis. However, metipranolol has been shown to increase fetal resorption, fetal death, and delayed development when administered orally to pregnant rabbits at 50 mg/kg during organogenesis.


Ophthalmic Dosage Forms

METIPRANOLOL HYDROCHLORIDE OPHTHALMIC SOLUTION

Note: The dosing and strengths usually available are expressed in terms of metipranolol base.


Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.3% solution of metipranolol (base) two times a day. {174}


Usual adult prescribing limits
Dosages above 1 drop of a 0.3% solution two times a day are not known to be of benefit. {174}

Usual pediatric dose
Safety and efficacy have not been established. {174}

Strength(s) usually available
U.S.—


0.3% (3 mg base per mL) (Rx) [OptiPranolol{174} ( benzalkonium chloride 0.004%) (glycerin) (sodium chloride) (edetate disodium ) (povidone) (hydrochloric acid and/or sodium hydroxide)]

Canada—
Not commercially available.

Packaging and storage:
Store below 40 °C (104 °F), preferably between 15 and 30 °C (59 and 86 °F), {174} in a well-closed container, unless otherwise specified by manufacturer. Protect from freezing.

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


TIMOLOL

Summary of Differences
Pharmacology/pharmacokinetics: Duration of action—Up to 24 hours.

Carcinogenicity: In a lifetime study in mice, timolol increased the incidence of malignant pulmonary tumors and mammary adenocarcinomas in female mice when administered orally at doses of 500 mg/kg per day, but not at 5 or 50 mg/kg per day.

Pregnancy: Studies in rats have shown that timolol at doses of up to 50 mg/kg per day (50 times the maximum recommended human oral dose) causes delayed fetal ossification; however, there were no adverse effects on postnatal development of offspring. Teratogenic studies in mice and rabbits have not shown that timolol at doses of up to 50 mg/kg per day causes fetal malformations. In mice, timolol at doses of 1 gram per kg per day (1000 times the maximum recommended human oral dose) was maternotoxic and resulted in increased incidence of fetal resorptions. In rabbits, timolol at doses 100 times the maximum recommended human oral dose caused increased incidence of fetal resorptions but not maternotoxicity.

Breast-feeding: Systemic timolol is distributed into breast milk. Problems in humans have not been documented for ophthalmic timolol; however, ophthalmic timolol may be systemically absorbed and distributed into the breast milk, possibly causing serious adverse reactions in the infants of nursing mothers.

Side/adverse effects: Transient blurred vision was reported frequently with the timolol maleate gel-forming solution. The blurred vision typically lasts from thirty seconds to five minutes. {236}

General dosing information: The gel-forming timolol ophthalmic solution should be inverted and shaken one time prior to each use. {236} If other topically administered ophthalmic medications are required, they should be administered at least ten minutes before the administration of the gel-forming timolol ophthalmic solution. {236}


When patients were transferred from the twice-daily administration of timolol maleate solution to the once-daily administration of timolol maleate gel-forming solution, the effect on ocular hypertension has remained consistant. {236}


Ophthalmic Dosage Forms

TIMOLOL HEMIHYDRATE OPHTHALMIC SOLUTION

Note: The dosing and strengths usually available are expressed in terms of timolol base.


Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.25 or 0.5% solution of timolol (base) twice a day. {242}


Usual pediatric dose
Ophthalmic antiglaucoma agent
Safety and efficacy have not been established. {242}


Strength(s) usually available
U.S.—


0.25% (2.5 mg base; 2.56 mg as hemihydrate) (Rx) [Betimol{242} (benzalkonium chloride 0.01%) (monosodium phosphate dihydrate) (disodium phosphate dihydrate )]


0.5% (5 mg base; 5.12 mg as hemihydrate) (Rx) [Betimol{242} (benzalkonium chloride 0.01%) (monosodium phosphate dihydrate) (disodium phosphate dihydrate )]

Canada—
Not commercially available in Canada.

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F). {242} Protect from freezing. Protect from light. {242}

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


TIMOLOL MALEATE OPHTHALMIC SOLUTION USP

Note: The dosing and strengths usually available are expressed in terms of timolol base.


Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.25 or 0.5% solution of timolol (base) one or two times a day. {175}


Usual pediatric dose
Ophthalmic antiglaucoma agent
Infants and children up to 10 years of age: Topical, to the conjunctiva, 1 drop of a 0.25% solution of timolol (base) one or two times a day. {92}

Children 10 years of age and older: See Usual adult and adolescent dose . {92}


Note: Nasolacrimal occlusion should be emphasized to patient. {92}


Strength(s) usually available
U.S.—


0.25% (2.5 mg base; 3.4 mg as maleate) (Rx) [Timoptic{175} (benzalkonium chloride 0.01%) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)] [Timoptic in Ocudose{175} (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)][Generic]{244}


0.5% (5 mg base; 6.8 mg as maleate) (Rx) [Timoptic{175} (benzalkonium chloride 0.01%) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)] [Timoptic in Ocudose{175} (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)][Generic]{244}

Canada—


0.25% (2.5 mg base; 3.4 mg as maleate) (Rx) [Apo-Timop{179} (benzalkonium chloride) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)] [Novo-Timol{240}] [Timoptic{239} (benzalkonium chloride) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)][Generic]{248}


0.5% (5 mg base; 6.8 mg as maleate) (Rx) [Apo-Timop{179} (benzalkonium chloride) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)] [Novo-Timol{240}] [Tim-AK{237} (benzalkonium chloride) (dibasic sodium phospate) (monobasic sodium phosphate) (sodium chloride) (sodium hydroxide)] [Timoptic{239} (benzalkonium chloride) (monobasic sodium phosphate) (dibasic sodium phosphate) (sodium hydroxide)][Generic]{238}

Packaging and storage:
Store between 15 and 30 °C (59 and 86 °F), {175} in a tight container, unless otherwise specified by manufacturer. Protect from freezing. Protect from light. {175}

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.


TIMOLOL MALEATE EXTENDED-RELEASE {249} OPHTHALMIC SOLUTION (GEL-FORMING)

Note: The dosing and strengths usually available are expressed in terms of timolol base.


Usual adult and adolescent dose
Ophthalmic antiglaucoma agent
Topical, to the conjunctiva, 1 drop of a 0.25 or 0.5% solution of timolol (base) once a day. {236}


Usual pediatric dose
Ophthalmic antiglaucoma agent
Safety and efficacy have not been established. {236}


Strength(s) usually available
U.S.—


0.25% (2.5 mg base; 3.4 mg as maleate) (Rx) [Timoptic-XE{236} (benzododecinium bromide 0.012%) ( gellan gum) (tromethamine) ( mannitol)]


0.5% (5 mg base; 6.8 mg as maleate) (Rx) [Timoptic-XE{236} (benzododecinium bromide 0.012%) ( gellan gum) (tromethamine) ( mannitol)]

Canada—


0.25% (2.5 mg base; 3.4 mg as maleate) (Rx) [Timoptic-XE{239} (benzododecinium bromide) (gellan gum ) (tromethamine) (mannitol )]


0.5% (5 mg base; 6.8 mg as maleate) (Rx) [Timoptic-XE{239} (benzododecinium bromide) (gellan gum ) (tromethamine) (mannitol )]

Packaging and storage:
Store between 15 and 25 °C (59 and 77 °F). {236} Protect from freezing. Protect from light. {236}

Auxiliary labeling:
   • For the eye.
   • Keep container tightly closed.
   • Shake once before use.



Revised: 05/25/2000



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  1. Open.
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  1. Open.
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  1. Open.
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  1. Reviewer comment for timolol, June 1992.
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  1. Zimmerman TJ, et al. Improving the therapeutic index of topically applied ocular drugs. Arch Ophthalmol 1984 Apr; 102(4): 551-3.
  1. Open.
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  1. Dosage form title change per USP Nomenclature Committee meeting of 5/19/99.
  1. Product Information: Betaxon™, levobetaxolol hydrochloride ophthalmic suspension. Alcon Laboratories, Fort Worth, TX, reviewed 4/2000.
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