WARNINGS
As with other topically applied ophthalmic drugs, BETAGAN
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 [See CONTRAINDICATIONS].
Cardiac Failure
Sympathetic stimulation may be essential for support
of the circulation in individuals with diminished myocardial
contractility, and its inhibition by beta-adrenergic receptor
blockade may precipitate more severe failure. In patients
without a History of Cardiac Failure: Continued depression
of the myocardium with beta-blocking agents over a period
of time can, in some cases, lead to cardiac failure. At
the first sign or symptom of cardiac failure, BETAGAN
should be discontinued.
Obstructive Pulmonary Disease
PATIENTS WITH CHRONIC OBSTRUCTlVE PULMONARY DISEASE (e.g.,
CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR MODERATE SEVERITY,
BRONCHOSPASTlC DISEASE OR A HISTORY OF BRONCHOSPASTlC
DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL
ASTHMA, IN WHICH BETAGAN IS CONTRAINDICATED, See CONTRAINDICATIONS),
SHOULD IN GENERAL NOT RECEIVE BETA BLOCKERS, INCLUDING
BETAGAN. However, if BETAGAN is deemed necessary in such
patients, then it should be administered cautiously since
it may block bronchodilation produced by endogenous and
exogenous catecholamine stimulation of beta2 receptors.
Major Surgery
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. This may augment the risk of general anesthesia
in surgical procedures. Some patients receiving beta-adrenergic
receptor blocking agents have been subject to protracted
severe hypotension during anesthesia. Difficulty in restarting
and maintaining the heartbeat has also been reported.
For these reasons, in patients undergoing elective surgery,
gradual withdrawal of beta-adrenergic blocking agents
may be appropriate.
If necessary during surgery, the effects of beta-adrenergic
blocking agents may be reversed by sufficient doses of
such agonists as isoproterenol, dopamine, dobutamine or
levarterenol (see OVERDOSAGE).
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 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.
These products contains sodium metabisulfite, a sulfite
that may cause allergic-type reactions including anaphylactic
symptoms and life-threatening or less severe asthmatic episodes
in certain susceptible people. The overall prevalence of
sulfite sensitivity in the general population is unknown
and probably low. Sulfite sensitivity is seen more frequently
in asthmatic than in nonasthmatic people.
PRECAUTIONS
General
BETAGAN (levobunolol HCl) Liquifilm sterile ophthalmic
solution should be used with caution in patients with
known hypersensitivity to other beta-adrenoceptor blocking
agents.
Use with caution in patients with known diminished pulmonary
function.
BETAGAN should be used with caution in patients who are
receiving a beta-adrenergic blocking agent orally, because
of the potential for additive effects on systemic beta-blockade
or on intraocular pressure. Patients should not typically
use two or more topical ophthalmic beta-adrenergic blocking
agents simultaneously.
Because of the potential effects of beta-adrenergic blocking
agents on blood pressure and pulse rates, these medications
must be used cautiously in patients with cerebrovascular
insufficiency. Should signs or symptoms develop that suggest
reduced cerebral blood flow while using BETAGAN, alternative
therapy should be considered.
In patients with angle-closure glaucoma, the immediate
objective of treatment is to reopen the angle. This requires,
in most cases, constricting the pupil with a miotic. BETAGAN
has liffle or no effect on the pupil. When BETAGAN is
used to reduce elevated intraocular pressure in angle-closure
glaucoma, it should be followed with a miotic and not
alone.
Muscle Weakness: Beta-adrenergic blockade
has been reported to potentiate muscle weakness consistent
with certain myasthenic symptoms (e.g. diplopia, ptosis
and generalized weakness).
Drug Interactions
Although BETAGAN used alone has little or no effect on
pupil size, mydriasis resulting from con-comitant therapy
with BETAGAN and epinephrine may occur.
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 marked
bradycardia, which may produce vertigo, syncope, or postural
hypotension.
Patients receiving beta-adrenergic blocking agents along
with either oral or intravenous calcium antagonists should
be monitored for possible atrioventricular conduction
disturbances, left ventricular failure, and hypotension.
In patients with impaired cardiac function, simultaneous
use should be avoided altogether.
The concomitant use of beta-adrenergic blocking agents
with digitalis and calcium antagonists may have additive
effects on prolonging atrioventricular conduction time.
Phenothiazine-related compounds and beta-adrenergic blocking
agents may have additive hypotensite effects due to the
inhibition of each other’s metabolism.
Risk of anaphylactic reaction: While
taking beta-blockers, patients with a history of severe
anaphylactic reaction to a variety of allergens may be
more reactive to repeated challenge, either accidental,
diagnostic, or therapeutic. Such patients may be unresponsive
to the usual doses of epinephrine used to treat allergic
reaction.
Animal Studies
No adverse ocular effects were observed in rabbits administered
BETAGAN topically in studies lasting one year in concentrations
up to 10 times the human dose concentration.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a lifetime oral study in mice, there were statistically
significant (p<e;0.05) increases in the incidence of
benign leiomyomas in female mice at 200 mg/kg/day (14,300
times the recommended human dose for glaucoma), but not
at 12 or 50 mg /kg/day (850 and 3,500 times the human
dose). In a two year oral study of levobunolol HCl in
rats, there was a statistically significant (p<e;O.05)
increase in the incidence of benign hepatomas in male
rats administered 12,800 times the recommended human dose
for glaucoma. Similar differences were not observed in
rats administered oral doses equivalent to 350 times to
2,000 times the recommended human dose for glaucoma.
Levobunolol did not show evidence of mutagenic activity
in a battery of microbiological and mammalian in vitro
and in vivo assays.
Reproduction and fertility studies in rats showed no
adverse effect on male or female fertility at doses up
to 1,800 times the recommended human dose for glaucoma.
Pregnancy Category C
Fetotoxicity (as evidenced by a greater number of resorption
sites) has been observed in rabbits when doses of levobunolol
HCl equivalent to 200 and 700 times the recommended dose
for the treatment of glaucoma were given. No fetotoxic
effects have been observed in similar studies with rats
at up to 1,800 times the human dose for glaucoma. Teratogenic
studies with levobunolol in rats at doses up to 25 mq/kg/day
(1,800 times the recommended human dose for glaucoma)
showed no evidence of fetal malformations. There were
no adverse effects on postnatal development of offspring.
It appears when results from studies using rats and studies
with other beta-adrenergic blockers are examined, that
the rabbit may be a particularly sensitive species. There
are no adequate and well-controlled studies in pregnant
women. BETAGAN should be used during pregnancy only if
the potential benefit justifies the potential risk to
the fetus.
Nursing Mothers
It is not known whether this drug is excreted in human
milk. Systemic beta-blockers and topical timolol maleate
are known to be excreted in human milk. Caution should
be exercised when BETAGAN is administered to a nursing
woman.
Pediatric Use
Safety and effectiveness in pediatric patients have not
been established.
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