BETAXOLOL HCL
DESCRIPTION:
OPTIPRESS Sterile Ophthalmic Solution contains betaxolol hydrochloride, a
cardioselective beta- adrenergic receptor blocking agent, in a sterile isotonic
solution. Betaxolol hydrochloride is a white, crystalline powder, soluble in
water, with a molecular weight of 343.89.
Chemical Name:
(+/- )-1-(p- (2-(Cyclopropylmethoxy)ethyl)phenoxy)-3-(isopropy lamino)-2-
propanol hydrochloride.
Each mL of OPTIPRESS Ophthalmic Solution (0.5%) contains: Active: 5.6 mg
betaxolol hydrochloride equivalent to betaxolol base 5 mg. Preservative:
Benzalkonium Chloride 0.01%. Inactives: Edetate Disodium, Sodium Chloride,
Hydrochloric Acid and/or Sodium Hydroxide (to adjust pH), and Purified Water.
ACTIONS/CLINICAL PHARMACOLOGY:
Betaxolol HCl, a cardioselective (beta- 1-adrenergic) receptor blocking agent,
does not have significant membrane-stabilizing (local anesthetic) activity and
is devoid of intrinsic sympathomimetic action. Orally administered beta-
adrenergic blocking agents reduce cardiac output in healthy subjects and
patients with heart disease. In patients with severe impairment of myocardial
function, beta-adrenergic receptor antagonists may inhibit the sympathetic
stimulatory effect necessary to maintain adequate cardiac function.
When instilled in the eye, OPTIPRESS Ophthalmic Solution has the action of
reducing elevated as well as normal intraocular pressure, whether or not
accompanied by glaucoma. Ophthalmic betaxolol has minimal effect on pulmonary
and cardiovascular parameters.
Ophthalmic betaxolol (one drop in each eye) was compared to timolol and placebo
in a three-way crossover study challenging nine patients with reactive airway
disease who were selected on the basis of having at least a 15% reduction in the
forced expiratory volume in one second (FEV1) after administration of ophthalmic
timolol. Betaxolol HCl had no significant effect on pulmonary function as
measured by FEV1, Forced Vital Capacity (FVC) and FEV1/VC. Additionally, the
action of isoproterenol, a beta stimulant, administered at the end of the study
was not inhibited by ophthalmic betaxolol. In contrast, ophthalmic timolol
significantly decreased these pulmonary functions.
No evidence of cardiovascular beta-adrenergic blockade during exercise was
observed with betaxolol in a double-masked, three-way crossover study in 24
normal subjects comparing ophthalmic betaxolol, timolol and placebo for effect
on blood pressure and heart rate. Mean arterial blood pressure was not affected
by any treatment; however, ophthalmic timolol produced a significant decrease in
the mean heart rate.
FEV(1)--PERCENT CHANGE FROM BASELINE(1)
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FEV(1)--PERCENT CHANGE FROM
Means
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Betaxolol 1.0%(a) Timolol 0.5% Placebo
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Baseline 1.6 1.4 1.4
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60 Minutes 2.3 -25.7* 5.8
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120 Minutes 1.6 -27.4* 7.5
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240 Minutes -6.4 -26.9* 6.9
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Isoproterenol(b) 36.1 -12.4* 42.8
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(1) Schoene, R. B., Et Al., Am. J. Ophthal. 97:86, 1984.
(a) Twice the clinical concentration.
(b) Inhaled at 240 minutes; measurement at 270 minutes.
* Timolol statistically different from betaxolol and placebo (p <0.05).
MEAN HEART RATES(1)
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TREATMENT
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Bruce Stress Exercise Test
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Minutes Betaxolol 1%(a) Timolol 0.5% Placebo
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0 79.2 79.3 81.2
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2 130.2 126.0 130.4
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4 133.4 128.0* 134.3
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6 136.4 129.2* 137.9
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8 139.8 131.8* 139.4
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10 140.8 131.8* 141.3
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(1) Atkins, J. M., Et Al., Am. J. Oph. 99:173-175, Feb., 1985.
(a) Twice the clinical concentration.
*Mean pulse rate significantly lower for timolol than betaxolol or placebo
(p <0.05).
CLINICAL STUDIES:
Optic nerve head damage and visual field loss are the result of a sustained
elevated intraocular pressure and poor ocular perfusion. OPTIPRESS Ophthalmic
Solution has the action of reducing elevated as well as normal intraocular
pressure, and the mechanism of ocular hypotensive action appears to be a
reduction of aqueous production as demonstrated by tonography and aqueous
fluorophotometry. The onset of action with OPTIPRESS Ophthalmic Solution can
generally be noted within 30 minutes and the maximal effect can usually be
detected 2 hours after topical administration. A single dose provides a 12-hour
reduction in intraocular pressure. Clinical observation of glaucoma patients
treated with OPTIPRESS Ophthalmic Solution for up to three years shows that the
intraocular pressure lowering effect is well maintained.
Clinical studies show that topical OPTIPRESS Ophthalmic Solution reduces mean
intraocular pressure 25% from baseline. In trials using 22 mmHg as a generally
accepted index of intraocular pressure control, OPTIPRESS Ophthalmic Solution was
effective in more than 94% of the population studied, of which 73% were treated
with the beta blocker alone. In controlled, double-masked studies, the magnitude
and duration of the ocular hypotensive effect of OPTIPRESS Ophthalmic Solution
and ophthalmic timolol solution were clinically equivalent.
OPTIPRESS Ophthalmic Solution has also been used successfully in glaucoma
patients who have undergone a laser trabeculoplasty and have needed additional
long-term ocular hypotensive therapy.
OPTIPRESS Ophthalmic Solution has been well- tolerated in glaucoma patients
wearing hard or soft contact lenses and in aphakic patients.
OPTIPRESS Ophthalmic Solution does not produce miosis or accommodative spasm
which are frequently seen with miotic agents. The blurred vision and night
blindness often associated with standard miotic therapy are not associated with
OPTIPRESS Ophthalmic Solution. Thus, patients with central lenticular opacities
avoid the visual impairment caused by a constricted pupil.
INDICATIONS AND USAGE:
OPTIPRESS Ophthalmic Solution has been shown to be effective in lowering
intraocular pressure and is indicated in the treatment of ocular hypertension
and chronic open-angle glaucoma. It may be used alone or in combination with
other anti-glaucoma drugs.
In clinical studies OPTIPRESS was safely used to lower intraocular pressure in
47 patients with both glaucoma and reactive airway disease who were followed for
a mean period of 15 months. However, caution should be used in treating patients
with severe reactive airway disease or a history of asthma.
CONTRAINDICATIONS:
Hypersensitivity to any component of this product. OPTIPRESS Ophthalmic Solution
is contraindicated in patients with sinus bradycardia, greater than a first
degree atrioventricular block, cardiogenic shock, or patients with overt cardiac
failure.
WARNINGS:
Topically applied beta-adrenergic blocking agents may be absorbed systemically.
The same adverse reactions found with systemic administration of beta-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 beta-adrenergic blocking agents.
OPTIPRESS Ophthalmic Solution has been shown to have a minor effect on heart rate
and blood pressure in clinical studies. Caution should be used in treating
patients with a history of cardiac failure or heart block. Treatment with
OPTIPRESS Ophthalmic Solution should be discontinued at the first signs of
cardiac failure.
PRECAUTIONS:
GENERAL: INFORMATION FOR PATIENTS. Do not touch dropper tip to any surface as
this may contaminate the solution.
DIABETES MELLITUS. Beta-adrenergic blocking agents should be administered with
caution in patients subject to spontaneous hypoglycemia or to diabetic patients
(especially those with labile diabetes) who are receiving insulin or oral
hypoglycemic agents. Beta-adrenergic receptor blocking agents may mask the signs
and symptoms of acute hypoglycemia.
THYROTOXICOSIS. Beta-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 beta-
adrenergic blocking agents, which might precipitate a thyroid storm.
MUSCLE WEAKNESS. Beta-adrenergic blockade has been reported to potentiate muscle
weakness consistent with certain myasthenic symptoms (e.g., diplopia, ptosis,
and generalized weakness).
MAJOR SURGERY. Consideration should be given to the gradual withdrawal of beta-
adrenergic blocking agents prior to general anesthesia because of the reduced
ability of the heart to respond to beta-adrenergically mediated sympathetic
reflex stimuli.
PULMONARY: Caution should be exercised in the treatment of glaucoma patients
with excessive restriction of pulmonary function. There have been reports of
asthmatic attacks and pulmonary distress during betaxolol treatment. Although
rechallenges of some such patients with ophthalmic betaxolol have not adversely
affected pulmonary function test results, the possibility of adverse pulmonary
effects in patients sensitive to beta blockers cannot be ruled out.
RISK FROM ANAPHYLACTIC REACTION: While taking beta-blockers, patients with a
history of atopy or a history of severe anaphylactic reaction to a variety of
allergens may be more reactive to repeated accidental, diagnostic, or
therapeutic challenge with such allergens. Such patients may be unresponsive to
the usual doses of epinephrine used to treat anaphylactic reactions.
DRUG INTERACTIONS: Patients who are receiving a beta-adrenergic blocking agent
orally and OPTIPRESS Ophthalmic Solution should be observed for a potential
additive effect either on the intraocular pressure or on the known systemic
effects of beta blockade.
Close observation of the patient is recommended when a beta-blocker is
administered to patients receiving catecholamine-depleting drugs such as
reserpine, because of possible additive effects and the production of
hypotension and/or bradycardia.
Betaxolol is an adrenergic blocking agent; therefore, caution should be
exercised in patients using concomitant adrenergic psychotropic drugs.
OCULAR: In patients with angle-closure glaucoma, the immediate treatment
objective is to re-open the angle by constriction of the pupil with a miotic
agent. Betaxolol has little or no effect on the pupil. When OPTIPRESS Ophthalmic
Solution is used to reduce elevated intraocular pressure in angle-closure
glaucoma, it should be used with a miotic and not alone.
CARCINOGENESIS, MUTAGENESIS, IMPAIRMENT OF FERTILITY: Lifetime studies with
betaxolol HCl have been completed in mice at oral doses of 6, 20 or 60 mg/kg/day
and in rats at 3, 12 or 48 mg/kg/day; betaxolol HCl demonstrated no carcinogenic
effect. Higher dose levels were not tested.
In a variety of In Vitro and In Vivo bacterial and mammalian cell assays,
betaxolol HCl was nonmutagenic.
PREGNANCY: PREGNANCY CATEGORY C: Reproduction, teratology, and peri- and
postnatal studies have been conducted with orally administered betaxolol HCl in
rats and rabbits. There was evidence of drug-related postimplantation loss in
rabbits and rats at dose levels above 12 mg/kg and 128 mg/kg, respectively.
Betaxolol HCl was not shown to be teratogenic, however, and there were no other
adverse effects on reproduction at subtoxic dose levels. There are no adequate
and well-controlled studies in pregnant women. OPTIPRESS Ophthalmic Solution
should be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus.
NURSING MOTHERS: It is not known whether betaxolol HCl is excreted in human
milk. Because many drugs are excreted in human milk, caution should be exercised
when OPTIPRESS Ophthalmic Solution is administered to nursing women.
PEDIATRIC USE: Safety and effectiveness in pediatric patients have not been
established.
DRUG INTERACTIONS:
Patients who are receiving a beta-adrenergic blocking agent orally and OPTIPRESS
Ophthalmic Solution should be observed for a potential additive effect either on
the intraocular pressure or on the known systemic effects of beta blockade.
Close observation of the patient is recommended when a beta-blocker is
administered to patients receiving catecholamine-depleting drugs such as
reserpine, because of possible additive effects and the production of
hypotension and/or bradycardia.
Betaxolol is an adrenergic blocking agent; therefore, caution should be
exercised in patients using concomitant adrenergic psychotropic drugs.
(See Also PRECAUTIONS)
ADVERSE REACTIONS:
The following adverse reactions have been reported in clinical trials with
OPTIPRESS Ophthalmic Solution.
OCULAR: Discomfort of short duration was experienced by one in four patients,
but none discontinued therapy; occasional tearing has been reported. Rare
instances of decreased corneal sensitivity, erythema, itching sensation, corneal
punctate staining, keratitis, anisocoria, edema, and photophobia have been
reported.
Additional medical events reported with other formulations of betaxolol include
blurred vision, foreign body sensation, dryness of the eyes, inflammation,
discharge, ocular pain, decreased visual acuity, and crusty lashes.
SYSTEMIC: Systemic reactions following administration of OPTIPRESS Ophthalmic
Solution 0.5% or OPTIPRESS S Ophthalmic Suspension 0.25% have been rarely
reported. These include:
CARDIOVASCULAR: Bradycardia, heart block and congestive failure.
PULMONARY: Pulmonary distress characterized by dyspnea, bronchospasm, thickened
bronchial secretions, asthma and respiratory failure.
CENTRAL NERVOUS SYSTEM: Insomnia, dizziness, vertigo, headaches, depression,
lethargy, and increase in signs and symptoms of myasthenia gravis.
OTHER: Hives, toxic epidermal necrolysis, hair loss and glossitis.
OVERDOSAGE:
No information is available on overdosage of humans. The oral LD50 of the drug
ranged from 350-920 mg/kg in mice and 860-1050 mg/kg in rats. The symptoms which
might be expected with an overdose of a systemically administered beta- 1-
adrenergic receptor blocker agent are bradycardia, hypotension and acute cardiac
failure. A topical overdose of OPTIPRESS Ophthalmic Solution may be flushed from
the eye(s) with warm tap water.
DOSAGE AND ADMINISTRATION:
The recommended dose is one to two drops of OPTIPRESS Ophthalmic Solution in the
affected eye(s) twice daily. In some patients, the intraocular pressure lowering
responses to OPTIPRESS Ophthalmic Solution may require a few weeks to stabilize.
As with any new medication, careful monitoring of patients is advised.
If the intraocular pressure of the patient is not adequately controlled on this
regimen, concomitant therapy with pilocarpine and other miotics, and/or
epinephrine and/or carbonic anhydrase inhibitors can be instituted.
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