A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Timoptic Warnings, Precautions, Pregnancy, Nursing, Abuse - Timolol Maleate
Timoptic Warnings, Precautions, Pregnancy, Nursing, Abuse - Timolol Maleate
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
Only: As with other topically applied ophthalmic
drugs, this drug 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 following systemic or ophthalmic
administration
of timolol maleate (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.
Tablets Only: Although beta
blockers should be avoided in overt congestive heart
failure, they can be used, if necessary, with caution in patients
with a history of failure
who are well-compensated, usually with digitalis
and diuretics. Both digitalis
and timolol maleate slow AV conduction. If cardiac
failure persists, therapy
with timolol maleate should be withdrawn.
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, timolol maleate should be discontinued.
Tablets Only: At
the first sign or symptom
of cardiac failure, patients receiving timolol maleate should be
digitalized and/or be given a diuretic, and the response
observed closely. If cardiac
failure continues, despite adequate digitalization
and diuretic therapy,
timolol maleate should be withdrawn.
| Exacerbation of Ischemic Heart Disease Following Abrupt
Withdrawal: For Tablets Only: Hypersensitivity
to catecholamines has been observed in patients withdrawn
from beta blocker
therapy; exacerbation
of angina and, in some cases, myocardial
infarction
have occurred after abrupt discontinuation of such
therapy. When discontinuing chronically administered timolol
maleate, particularly in patients with ischemic heart
disease, the dosage
should be gradually reduced over a period
of one to two weeks and the patient
should be carefully monitored. If angina
markedly worsens or acute
coronary insufficiency develops, timolol maleate administration
should be reinstituted promptly, at least temporarily, and
other measures appropriate for the management of unstable
angina should be
taken. Patients should be warned against interruption or discontinuation
of therapy without the physician's advice. Because coronary
artery disease
is common and may be unrecognized, it may be prudent not to
discontinue timolol maleate therapy abruptly even in patients
treated only for hypertension. |
Obstructive Pulmonary Disease
PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (E.G.,
CHRONIC BRONCHITIS, EMPHYSEMA) OF MILD OR
MODERATE SEVERITY, BRONCHOSPASTIC DISEASE, OR A HISTORY OF BRONCHOSPASTIC
DISEASE (OTHER THAN BRONCHIAL ASTHMA OR A HISTORY OF BRONCHIAL ASTHMA,
IN WHICH TIMOLOL MALEATE IS CONTRAINDICATED, (SEE CONTRAINDICATIONS),
SHOULD, IN GENERAL, NOT RECEIVE BETA BLOCKERS, INCLUDING TIMOLOL
MALEATE. Additional Information for Tablets: However, if
timolol maleate is necessary in such patients, then the drug
should be administered with caution 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 experienced protracted, severe hypotension
during anesthesia. Difficulty in restarting and maintaining the
heartbeat has also
been reported. For these reasons, in patients undergoing elective
surgery, some authorities recommend gradual withdrawal
of beta-adrenergic receptor blocking
agents.
If necessary during surgery, the effects of beta-adrenergic blocking
agents may be reversed by sufficient doses of adrenergic
agonists for the ophthalmic solutions and ophthalmic
gel forming solution; and
such agonists as isoproterenol, dopamine, dobutamine or levarterenol
for the tablets (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 hypoglycemia 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.
PRECAUTIONS
General
Muscle Weakness: Beta-adrenergic blockade
has been reported to potentiate
muscle weakness
consistent with certain myasthenic symptoms (e.g., diplopia,
ptosis, and generalized weakness). Timolol has been reported rarely
to increase muscle weakness
in some patients with myasthenia gravis or myasthenic symptoms.
Tablets
Impaired Hepatic or Renal Function: Since timolol
maleate is partially metabolized in the liver
and excreted mainly by the kidneys, dosage reductions may be necessary
when hepatic and/or
renal insufficiency is
present.
Dosing in the Presence of Marked Renal Failure: Although
the pharmacokinetics
of timolol maleate are not greatly altered by renal impairment,
marked hypotensive
responses have been seen in patients with marked renal
impairment undergoing
dialysis after 20 mg
doses. Dosing in such patients should therefore be especially cautious.
Cerebrovascular Insufficiency: Because of potential
effects of beta-adrenergic blocking
agents relative to blood
pressure and pulse,
these agents should be used with caution in patients with cerebrovascular
insufficiency. If signs or symptoms suggesting reduced cerebral
blood flow are observed,
consideration should be given to discontinuing these agents.
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
Because of potential
effects of beta-adrenergic blocking
agents on blood pressure and pulse, these agents should be used
with caution in patients with cerebrovascular
insufficiency. If signs or symptoms suggesting reduced cerebral
blood wflow
develop following initiation of therapy with timolol maleate, alternative
therapy should be considered.
Choroidal detachment
after filtration
procedures has been reported with the administration
of aqueous suppressant
therapy (e.g., timolol).
Angle-closure Glaucoma: In
patients with angle-closure glaucoma, the immediate
objective of treatment
is to reopen the angle. This requires constricting the pupil. Timolol
maleate has little or no effect on the pupil. Timolol maleate should
not be used alone in the treatment of angle-closure glaucoma.
Anaphylaxis: While taking beta-blockers, patients
with a history of atopy or a history of severe anaphylactic reactions
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.
Additional Information for Ophthalmic Solution (not including
preservative-free) and Ophthalmic Gel Forming Solution:
There have been reports of bacterial keratitis
associated with the use of multiple dose containers of topical
ophthalmic products.
These containers had been inadvertently contaminated by patients
who, in most cases, had a concurrent corneal disease
or a disruption of the ocular
epithelial surface (see
Information for the Patient).
Information for the Patient
Ophthalmic Solutions and Ophthalmic Gel Forming Solution
Patients should be instructed to avoid allowing the tip
of the dispensing container to contact
the eye or surrounding structures.
Patients should also be instructed that ocular
solutions, if handled improperly or if the tip
of the dispensing container
contacts the eye or surrounding
structures, can become contaminated by common bacteria
known to cause ocular
infections. Serious damage to the eye
and subsequent loss of vision
may result from using contaminated solutions (see General).
Additional Information for Ophthalmic Solutions:
Patients with bronchia asthma, a history of bronchial
asthma, severe chronic
obstructive pulmonary disease, sinus
bradycardia, second or third degree
atrioventricular block, or cardiac
failure should be advised
not to take this produce
(see CONTRAINDICATIONS).
Patients should be advised that timolol maleate contains benzalkonium
chloride which may be absorbed by soft
contact lenses. Contact
lenses should be removed prior to administration
of the solution. Lenses may be reinserted 15 minutes following timolol
maleate administration.
Additional Information for Ophthalmic Solution: (Not
for preservative-free ophthalmic
solution.) Patients should also be advised that if they have
ocular surgery or develop
an intercurrent
ocular condition (e.g., trauma
or infection), they should immediately seek their physician's advice
concerning the continued use of the present
multidose container.
Preservative-Free Ophthalmic Solution
Patients should be instructed about the use of preservative-free
timolol maleate in Ocudose.
Since sterility cannot be maintained after the individual unit
is opened, patients should be instructed to use the product
immediately after opening, and to discard the individual unit
and any remaining contents immediately after use.
Ophthalmic Gel Forming Solution
Patients should be instructed to invert
the closed container
and shake once before each use. It is not necessary to shake the
container more than
once.
Patients requiring concomitant
topical ophthalmic
medications should be instructed to administer these at least 10
minutes before instilling timolol maleate.
Patients with bronchial
asthma, a history of bronchial
asthma, severe chronic obstructive pulmonary disease, sinus
bradycardia, second or third degree atrioventricular
block, or cardiac failure
should be advised not to take
this product (see CONTRAINDICATIONS).
Transient blurred vision, generally lasting from 30 seconds to
5 minutes, following instillation, and potential
visual disturbances may
impair the ability to perform hazardous tasks such as operating
machinery or driving a motor
vehicle.
Carcinogenesis, Mutagenesis, and Impairment of Fertility
In a two-year study of timolol maleate administered orally to rats,
there was a statistically significant
increase in the incidence
of adrenal pheochromocytomas in male
rats administered 300 mg/kg/day (250 times* the maximum recommended
human dose
for the tablets, and approximately 42,000 times the systemic
exposure following
the maximum recommended
human ophthalmic dose
for the ophthalmic
solutions and gel forming
solution). Similar differences were not observed in rats administered
oral doses equivalent
to approximately 20 or 80 times* the maximum
recommended human dose
for the tablets, and approximately 14,000 times the maximum
recommended human ophthalmic
dose for the ophthalmic
solutions and gel forming
solution.
In a lifetime oral study
in mice, there were statistically significant increases in the incidence
of benign and malignant
pulmonary tumors, benign uterine polyps and mammary adenocarcinoma
in female mice at 500
mg/kg/day (approximately 400 times* the maximum
recommended human dose
for the tablets, and approximately 71,000 times the systemic
exposure following
the maximum recommended human
ophthalmic dose
for the ophthalmic
solutions and gel forming solution), but not at 5 or 50 mg/kg/day
(approximately 700 or 7000, respectively, times, the systemic
exposure following
the maximum recommended
human ophthalmic
dose for the ophthalmic
solutions and gel forming
solution). In a subsequent study in female
mice, in which post-mortem examinations were limited to the uterus
and the lungs, a statistically significant
increase in the incidence
of pulmonary tumors was again observed at 500 mg/kg/day.
The increased occurrence of mammary adenocarcinomas was associated
with elevations in serum
prolactin, which occurred in female
mice administered oral timolol at 500 mg/kg, but not at doses of
5 or 50 mg/kg/day. An increased
incidence of mammary adenocarcinomas in rodents has been associated
with administration of several other therapeutic
agents that elevate serum
prolactin, but no correlation
between serum prolactin
levels and mammary tumors has been established in man. Furthermore,
in adult human
female subjects who received
oral dosages of up to 60
mg of timolol maleate (the
maximum recommended
human oral dosage), there
were no clinically meaningful changes in serum prolactin.
Timolol maleate was devoid of mutagenic potential
when evaluated in vivo (mouse) in the micronucleus
test and cytogenetic assay
(doses up to 800 mg/kg) and in vitro in a neoplastic cell
transformation assay (up to 100 mcg/ml). In
Ames tests, the highest concentrations of timolol employed, 5000
or 10,000 mcg/plate, were associated with statistically significant
elevations of revertants observed with tester strain
TA 100 (in seven replicate assays), but not in the remaining three
strains. In the assays with tester strain
TA 100, no consistent dose
response relationship
was observed, nor did the ratio
of test to control
revertants reach 2. A ratio
of 2 is usually considered the criterion
for a positive Ames
test.
Reproduction and fertility studies in rats showed no adverse effect
on male or female
fertility at doses up to 125 times* the maximum
recommended human dose
for the tablets, and up to 21,000 times the systemic
exposure following the maximum
recommended human ophthalmic
dose for the ophthalmic
solutions and gel forming
solution.
*Based on a patient
weight of 50 kg
Pregnancy, Teratogenic Effects, Pregnancy Category C
Teratogenicity studies with timolol in mice, rats, and rabbits
at doses up to 50 mg/kg/day (40 times the maximum
recommended human dose
for the tablets, and 7000 times the systemic
exposure following
the maximum recommended
human ophthalmic
dose for the ophthalmic
solutions and gel forming
solution) demonstrated no evidence
of fetal malformations.
Although delayed fetal ossification was observed at this dose
in rats, there were no adverse effects on postnatal
development of offspring.
Doses of 1000 mg/kg/day (approximately 830 times the maximum
recommended human dose
for the tablets, and 142,000 times the systemic
exposure following
the maximum recommended
human ophthalmic dose
for the ophthalmic
solutions and gel forming
solution) were maternotoxic in mice and resulted in an increased
number of fetal
resorptions. Increased fetal resorptions were also seen in rabbits
at doses of approximately 40 times the maximum
recommended human dose
for the tablets, and 14,000 times the systemic
exposure following
the maximum recommended
human ophthalmic dose
for the ophthalmic
solutions and gel forming
solution, in this case without apparent
maternotoxicity. There are no adequate and well-controlled studies
in pregnant women.
Timolol maleate should be used during pregnancy only if the potential
benefit justifies the
potential risk
to the fetus.
Nursing Mothers
Timolol maleate has been detected in human
milk following oral
and ophthalmic drug administration. Because of the potential
for serious adverse reactions from timolol maleate in nursing
infants, a decision should be made whether to discontinue nursing
or to discontinue the drug, taking into account the importance of
the drug to the mother.
Pediatric Use
Safety and effectiveness
in pediatric patients
have not been established.
Geriatric Use
Tablets, Ophthalmic Solution, and Ophthalmic Gel Forming
Solution: (Not for preservative-free ophthalmic
solution.) Of the total number of patients in clinical
studies of timolol maleate, 46% were 65 years of age and over, while
14% were 75 years of age
and over. No overall differences in effectiveness
or safety were observed between these patients and younger patients,
but greater sensitivity of some older individuals to the product
cannot be ruled out.
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