TIMOPTIC® in OCUDOSE®0.25% AND 0.5% (TIMOLOL
MALEATE OPHTHALMIC SOLUTION)PRESERVATIVE-FREE STERILE OPHTHALMIC
SOLUTIONin a Sterile Ophthalmic Unit Dose Dispenser
timolol maleate solution Merck & Co., Inc.
TIMOPTIC® in OCUDOSE® 0.25% AND 0.5% (TIMOLOL
MALEATE OPHTHALMIC SOLUTION) PRESERVATIVE-FREE STERILE OPHTHALMIC
SOLUTION in a Sterile Ophthalmic Unit Dose Dispenser
Timolol maleate is a non-selective beta-adrenergic
receptor blocking agent. Its chemical name is (-)-1-(tert-butylamino)-3-[(4-morpholino-1,2,5-thiadiazol-3-yl)oxy]-2-propanol
maleate (1:1) (salt). Timolol maleate possesses an asymmetric carbon
atom in its structure and is provided as the levo-isomer. The optical
rotation of timolol maleate is:
25° [α] in
1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°). 405 nm
Its molecular formula is C13H24N4O3S•C4H4O4 and its structural formula is:
Timolol maleate has a molecular weight
of 432.50. It is a white, odorless, crystalline powder which is soluble
in water, methanol, and alcohol. Timolol maleate is stable at room
Timolol maleate ophthalmic solution
is supplied in two formulations: Ophthalmic Solution TIMOPTIC1 (timolol maleate ophthalmic
solution), which contains the preservative benzalkonium chloride;
and Ophthalmic Solution TIMOPTIC1(timolol maleate ophthalmic solution), the preservative-free formulation.
Preservative-free Ophthalmic Solution TIMOPTIC is supplied
in OCUDOSE1, a unit dose
container, as a sterile, isotonic, buffered, aqueous solution of timolol
maleate in two dosage strengths: Each mL of Preservative-free TIMOPTIC
in OCUDOSE 0.25% contains 2.5 mg of timolol (3.4 mg of timolol maleate).
The pH of the solution is approximately 7.0, and the osmolarity is
252-328 mOsm. Each mL of Preservative-free TIMOPTIC in OCUDOSE 0.5%
contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients:
monobasic and dibasic sodium phosphate, sodium hydroxide to adjust
pH, and water for injection.
Timolol maleate is a beta1 and beta2 (non-selective) adrenergic receptor blocking agent that does
not have significant intrinsic sympathomimetic, direct myocardial
depressant, or local anesthetic (membrane-stabilizing) activity.
Beta-adrenergic receptor blockade reduces cardiac output
in both healthy subjects and patients with heart disease. In patients
with severe impairment of myocardial function, beta-adrenergic receptor
blockade may inhibit the stimulatory effect of the sympathetic nervous
system necessary to maintain adequate cardiac function.
Beta-adrenergic receptor blockade in the bronchi and bronchioles
results in increased airway resistance from unopposed parasympathetic
activity. Such an effect in patients with asthma or other bronchospastic
conditions is potentially dangerous.
(timolol maleate ophthalmic solution), when applied topically on the
eye, has the action of reducing elevated as well as normal intraocular
pressure, whether or not accompanied by glaucoma. Elevated intraocular
pressure is a major risk factor in the pathogenesis of glaucomatous
visual field loss. The higher the level of intraocular pressure, the
greater the likelihood of glaucomatous visual field loss and optic
The onset of reduction in intraocular
pressure following administration of TIMOPTIC (timolol maleate ophthalmic
solution) can usually be detected within one-half hour after a single
dose. The maximum effect usually occurs in one to two hours and significant
lowering of intraocular pressure can be maintained for periods as
long as 24 hours with a single dose. Repeated observations over a
period of one year indicate that the intraocular pressure-lowering
effect of TIMOPTIC (timolol maleate ophthalmic solution) is well maintained.
The precise mechanism of the ocular hypotensive action
of TIMOPTIC (timolol maleate ophthalmic solution) is not clearly established
at this time. Tonography and fluorophotometry studies in man suggest
that its predominant action may be related to reduced aqueous formation.
However, in some studies a slight increase in outflow facility was
In a study of plasma drug concentration in six subjects,
the systemic exposure to timolol was determined following twice daily
administration of TIMOPTIC 0.5%. The mean peak plasma concentration
following morning dosing was 0.46 ng/mL and following afternoon dosing
was 0.35 ng/mL.
In controlled multiclinic studies in patients with
untreated intraocular pressures of 22 mmHg or greater, TIMOPTIC (timolol
maleate ophthalmic solution) 0.25 percent or 0.5 percent administered
twice a day produced a greater reduction in intraocular pressure than
1, 2, 3, or 4 percent pilocarpine solution administered four times
a day or 0.5, 1, or 2 percent epinephrine hydrochloride solution administered
twice a day.
In these studies, TIMOPTIC (timolol
maleate ophthalmic solution) was generally well tolerated and produced
fewer and less severe side effects than either pilocarpine or epinephrine.
A slight reduction of resting heart rate in some patients receiving
TIMOPTIC (timolol maleate ophthalmic solution) (mean reduction 2.9
beats/minute standard deviation 10.2) was observed.
INDICATIONS AND USAGE
Preservative-free TIMOPTIC in OCUDOSE is indicated
in the treatment of elevated intraocular pressure in patients with
ocular hypertension or open-angle glaucoma.
Preservative-free TIMOPTIC in OCUDOSE may be used when a patient
is sensitive to the preservative in TIMOPTIC (timolol maleate ophthalmic
solution), benzalkonium chloride, or when use of a preservative-free
topical medication is advisable.
Preservative-free TIMOPTIC in OCUDOSE is contraindicated
in patients with (1) bronchial asthma; (2) a history of bronchial
asthma; (3) severe chronic obstructive pulmonary disease (see WARNINGS); (4) sinus bradycardia; (5)
second or third degree atrioventricular block; (6) overt cardiac failure
(see WARNINGS); (7) cardiogenic shock; or (8)
hypersensitivity to any component of this product.
As with many topically applied ophthalmic drugs,
this drug is 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).
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, Preservative-free TIMOPTIC in
OCUDOSE should be discontinued.
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 TIMOPTIC
in OCUDOSE is contraindicated [see CONTRAINDICATIONS]) should, in
general, not receive beta-blockers, including Preservative-free TIMOPTIC
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.
necessary during surgery, the effects of beta-adrenergic blocking
agents may be reversed by sufficient doses of adrenergic agonists.
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.
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 that might precipitate
a thyroid storm.
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 flow develop following
initiation of therapy with Preservative-free TIMOPTIC in OCUDOSE,
alternative therapy should be considered.
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. TIMOPTIC
in OCUDOSE should not be used alone in the treatment of angle-closure
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.
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.
Information for Patients
Patients should be instructed about the use of Preservative-free
TIMOPTIC 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
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.
Although TIMOPTIC (timolol maleate ophthalmic solution)
used alone has little or no effect on pupil size, mydriasis resulting
from concomitant therapy with TIMOPTIC (timolol maleate ophthalmic
solution) and epinephrine has been reported occasionally.
agents: Patients who are receiving a beta-adrenergic blocking
agent orally and Preservative-free TIMOPTIC in OCUDOSE should be observed
for potential additive effects of beta-blockade, both systemic and
on intraocular pressure. The concomitant use of two topical beta-adrenergic
blocking agents is not recommended.
Calcium antagonists: Caution should
be used in the coadministration of beta-adrenergic blocking agents,
such as Preservative-free TIMOPTIC in OCUDOSE, and oral or intravenous
calcium antagonists, because of possible atrioventricular conduction
disturbances, left ventricular failure, and hypotension. In patients
with impaired cardiac function, coadministration should be avoided.
Catecholamine-depleting drugs: 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 result in vertigo,
syncope, or postural hypotension.
Digitalis and calcium antagonists: The
concomitant use of beta-adrenergic blocking agents with digitalis
and calcium antagonists may have additive effects in prolonging atrioventricular
CYP2D6 inhibitors: Potentiated systemic beta-blockade (e.g.,
decreased heart rate, depression) has been reported during combined
treatment with CYP2D6 inhibitors (e.g., quinidine, SSRIs) and timolol.
beta-adrenergic blocking agents may exacerbate the rebound hypertension
which can follow the withdrawal of clonidine. There have been no reports
of exacerbation of rebound hypertension with ophthalmic timolol maleate.
Carcinogenesis, Mutagenesis, Impairment of Fertility
In a two-year oral 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 (approximately 42,000 times the systemic exposure following
the maximum recommended human ophthalmic dose). Similar differences
were not observed in rats administered oral doses equivalent to approximately
14,000 times the maximum recommended human ophthalmic dose.
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 adenocarcinomas in female
mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure
following the maximum recommended human ophthalmic dose), but not
at 5 or 50 mg/kg/day (approximately 700 or 7,000 times, respectively,
the systemic exposure following the maximum recommended human ophthalmic
dose). 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/day, 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 humans. 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
tested 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, 5,000 or 10,000 mcg/plate, were associated with
statistically significant elevations of revertants observed with tester
strain TA100 (in seven replicate assays), but not in the remaining
three strains. In the assays with tester strain TA100, no consistent
dose response relationship was observed, and the ratio of test to
control revertants did not reach 2. A ratio of 2 is usually considered
the criterion for a positive Ames test.
and fertility studies in rats demonstrated no adverse effect on male
or female fertility at doses up to 21,000 times the systemic exposure
following the maximum recommended human ophthalmic dose.
Pregnancy Category C.
studies with timolol in mice, rats and rabbits at oral doses up to
50 mg/kg/day (7,000 times the systemic exposure following the maximum
recommended human ophthalmic dose) 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 (142,000 times the systemic
exposure following the maximum recommended human ophthalmic dose)
were maternotoxic in mice and resulted in an increased number of fetal
resorptions. Increased fetal resorptions were also seen in rabbits
at doses of 14,000 times the systemic exposure following the maximum
recommended human ophthalmic dose, in this case without apparent maternotoxicity.
There are no adequate and well-controlled studies in pregnant
women. Preservative-free TIMOPTIC in OCUDOSE should be used during
pregnancy only if the potential benefit justifies the potential risk
to the fetus.
Timolol maleate has been detected in human milk following
oral and ophthalmic drug administration. Because of the potential
for serious adverse reactions from timolol 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.
Safety and effectiveness in pediatric patients have
not been established.
No overall differences in safety or effectiveness
have been observed between elderly and younger patients.
The most frequently reported adverse experiences
have been burning and stinging upon instillation (approximately one
in eight patients).
The following additional
adverse experiences have been reported less frequently with ocular
administration of this or other timolol maleate formulations:
diarrhea, dyspepsia, anorexia, and dry mouth.
Systemic lupus erythematosus.
increase in signs and symptoms of myasthenia gravis, paresthesia,
somnolence, insomnia, nightmares, behavioral changes and psychic disturbances
including depression, confusion, hallucinations, anxiety, disorientation,
nervousness, and memory loss.
Alopecia and psoriasiform rash or exacerbation of psoriasis.
Signs and symptoms
of systemic allergic reactions including anaphylaxis, angioedema,
urticaria, and localized and generalized rash.
Bronchospasm (predominantly in
patients with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, cough and upper respiratory infections.
Masked symptoms of hypoglycemia
in diabetic patients (see WARNINGS).
Signs and symptoms of ocular irritation
including conjunctivitis, blepharitis, keratitis, ocular pain, discharge
(e.g., crusting), foreign body sensation, itching and tearing, and
dry eyes; ptosis; decreased corneal sensitivity; cystoid macular edema;
visual disturbances including refractive changes and diplopia; pseudopemphigoid;
choroidal detachment following filtration surgery (see PRECAUTIONS, General); and tinnitus.
Retroperitoneal fibrosis, decreased
libido, impotence, and Peyronie's disease.
following additional adverse effects have been reported in clinical
experience with ORAL timolol maleate or other ORAL beta blocking agents,
and may be considered potential effects of ophthalmic timolol maleate: Allergic: Erythematous rash, fever combined
with aching and sore throat, laryngospasm with respiratory distress; Body as a Whole: Extremity pain, decreased
exercise tolerance, weight loss; Cardiovascular: Worsening of arterial insufficiency, vasodilatation; Digestive: Gastrointestinal pain, hepatomegaly,
vomiting, mesenteric arterial thrombosis, ischemic colitis; Hematologic: Nonthrombocytopenic purpura;
thrombocytopenic purpura; agranulocytosis; Endocrine: Hyperglycemia, hypoglycemia; Skin: Pruritus, skin irritation, increased
pigmentation, sweating; Musculoskeletal: Arthralgia; Nervous System/Psychiatric: Vertigo, local weakness, diminished concentration, reversible mental
depression progressing to catatonia, an acute reversible syndrome
characterized by disorientation for time and place, emotional lability,
slightly clouded sensorium, and decreased performance on neuropsychometrics; Respiratory: Rales, bronchial obstruction; Urogenital: Urination difficulties.
There have been reports of inadvertent overdosage
with Ophthalmic Solution TIMOPTIC (timolol maleate ophthalmic solution)
resulting in systemic effects similar to those seen with systemic
beta-adrenergic blocking agents such as dizziness, headache, shortness
of breath, bradycardia, bronchospasm, and cardiac arrest (see also ADVERSE REACTIONS).
been reported with Tablets BLOCADREN1 (timolol maleate tablets). A 30 year
old female ingested 650 mg of BLOCADREN (maximum recommended oral
daily dose is 60 mg) and experienced second and third degree heart
block. She recovered without treatment but approximately two months
later developed irregular heartbeat, hypertension, dizziness, tinnitus,
faintness, increased pulse rate, and borderline first degree heart
An in vitro hemodialysis study, using 14C timolol added to human
plasma or whole blood, showed that timolol was readily dialyzed from
these fluids; however, a study of patients with renal failure showed
that timolol did not dialyze readily.
DOSAGE AND ADMINISTRATION
Preservative-free TIMOPTIC in OCUDOSE is a sterile
solution that does not contain a preservative. The solution from one
individual unit is to be used immediately after opening for administration
to one or both eyes. Since sterility cannot be guaranteed after the
individual unit is opened, the remaining contents should be discarded
immediately after administration.
TIMOPTIC in OCUDOSE is available in concentrations of 0.25 and 0.5
percent. The usual starting dose is one drop of 0.25 percent Preservative-free
TIMOPTIC in OCUDOSE in the affected eye(s) administered twice a day.
Apply enough gentle pressure on the individual container to obtain
a single drop of solution. If the clinical response is not adequate,
the dosage may be changed to one drop of 0.5 percent solution in the
affected eye(s) administered twice a day.
in some patients the pressure-lowering response to Preservative-free
TIMOPTIC in OCUDOSE may require a few weeks to stabilize, evaluation
should include a determination of intraocular pressure after approximately
4 weeks of treatment with Preservative-free TIMOPTIC in OCUDOSE.
If the intraocular pressure is maintained at satisfactory
levels, the dosage schedule may be changed to one drop once a day
in the affected eye(s). Because of diurnal variations in intraocular
pressure, satisfactory response to the once-a-day dose is best determined
by measuring the intraocular pressure at different times during the
Dosages above one drop of 0.5 percent TIMOPTIC
(timolol maleate ophthalmic solution) twice a day generally have not
been shown to produce further reduction in intraocular pressure. If
the patient's intraocular pressure is still not at a satisfactory
level on this regimen, concomitant therapy with other agent(s) for
lowering intraocular pressure can be instituted taking into consideration
that the preparation(s) used concomitantly may contain one or more
preservatives. The concomitant use of two topical beta-adrenergic
blocking agents is not recommended. (See PRECAUTIONS, Drug Interactions, Beta-adrenergic blocking agents.)
Preservative-free Sterile Ophthalmic Solution TIMOPTIC
in OCUDOSE is a clear, colorless to light yellow solution.
No. 9689 — Preservative-free TIMOPTIC, 0.25% timolol
equivalent, is supplied in OCUDOSE, a clear low density polyethylene
unit dose container. Each individual unit contains 0.2 mL of solution,
and is available in a foil laminate overwrapped pouch as follows:
NDC 0006-9689-60; 60 Individual Unit Doses.
No. 9690 — Preservative-free TIMOPTIC, 0.5% timolol
equivalent, is supplied in OCUDOSE, a clear low density polyethylene
unit dose container. Each individual unit contains 0.2 mL of solution,
and is available in a foil laminate overwrapped pouch as follows:
NDC 0006-9690-60; 60 Individual Unit Doses.
Store at room temperature, 15-30°C (59-86°F).
Protect from freezing. Protect from light.
evaporation can occur through the unprotected polyethylene unit dose
container and prolonged exposure to direct light can modify the product,
the unit dose container should be kept in the protective foil overwrap
and used within one month after the foil package has been opened.