Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1279
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TIMOPTIC (Solution)
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INSTRUCTIONS FOR USE: Please follow these instructions carefully when using
TIMOPTIC. Use TIMOPTIC as prescribed by your doctor. WARNING: Keep out of reach of children. If you have any questions about the use of TIMOPTIC, please
consult your doctor. Issued September 2005 9391006 Manuf. for:MERCK&CO., Inc., Whitehouse Station, NJ 08889, USA By: Laboratories Merck Sharp&Dohme-Chibret 63963 Clermont-Ferrand Cedex 9, France
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TIMOPTIC Ophthalmic Solution is available in concentrations
of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25
percent TIMOPTIC in the affected eye(s) twice a day. 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) twice a day. Since in some patients the pressure-lowering response
to TIMOPTIC may require a few weeks to stabilize, evaluation should
include a determination of intraocular pressure after approximately
4 weeks of treatment with TIMOPTIC. 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 day. Dosages above one drop of 0.5 percent TIMOPTIC 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. The concomitant use
of two topical beta-adrenergic blocking agents is not recommended.
(See PRECAUTIONS, Drug
Interactions, blocking agents.)
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TIMOPTIC(timolol maleate ophthalmic
solution) 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: Its molecular formula is CHNOS���CHOand
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.
TIMOPTIC is stable at room temperature. TIMOPTIC
Ophthalmic Solution is supplied as a sterile, isotonic, buffered,
aqueous solution of timolol maleate in two dosage strengths: Each
mL of TIMOPTIC 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 274-328 mOsm. Each mL of TIMOPTIC 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. Benzalkonium chloride 0.01%
is added as preservative.
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Mechanism of Action: Timolol maleate is a betaand beta(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. TIMOPTIC
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 nerve damage. The onset of reduction in intraocular pressure following
administration of TIMOPTIC 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 is well maintained. The precise mechanism of the ocular hypotensive action
of TIMOPTIC 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 also observed.<br/>Pharmacokinetics: 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.<br/>Clinical Studies: In controlled multiclinic studies in patients with
untreated intraocular pressures of 22 mmHg or greater, TIMOPTIC
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 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 (mean reduction 2.9 beats/minute standard deviation
10.2) was observed.
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TIMOPTIC is contraindicated in patients with (1) bronchial
asthma; (2) a history of bronchial asthma; (3) severe chronic
obstructive pulmonary disease ; (4) sinus bradycardia; (5) second or third degree atrioventricular
block; (6) overt cardiac failure ; (7) cardiogenic shock; or (8) hypersensitivity
to any component of this product.
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Sterile Ophthalmic Solution TIMOPTIC is a clear,
colorless to light yellow solution. No. 8895���TIMOPTIC Ophthalmic Solution, 0.25% timolol equivalent, is supplied
in an OCUMETERPLUS container, a white, translucent, HDPE plastic ophthalmic dispenser
with a controlled drop tip and a white polystyrene cap with yellow
label as follows: NDC 0006-8895-35, 5 mL in a 7.5 mL capacity bottle No. 8896���TIMOPTIC Ophthalmic Solution, 0.5%
timolol equivalent, is supplied in an OCUMETER PLUS
container, a white translucent, HDPE plastic ophthalmic dispenser
with a controlled drop tip and a white polystyrene cap with yellow
label as follows: NDC 0006-8896-35, 5 mL in a 7.5 mL capacity bottle NDC 0006-8896-36,
10 mL in an 18 mL capacity bottle.<br/>Storage: Store at room temperature, 15-30��C (59-86��F).
Protect from freezing. Protect from light. Manuf.
for:MERCK&CO., Inc., Whitehouse Station, NJ 08889, USA By: Laboratories Merck Sharp&Dohme-Chibret 63963 Clermont-Ferrand Cedex 9, France Issued September 2005 324A-07/05
514041Z 9391006
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General: 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 TIMOPTIC, alternative therapy should be
considered. 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. 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. TIMOPTIC 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. 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.<br/>Information for Patients: 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. 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. 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. Patients should be advised that TIMOPTIC 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 TIMOPTIC administration.<br/>Drug Interactions: Although TIMOPTIC used alone has little or no effect
on pupil size, mydriasis resulting from concomitant therapy with TIMOPTIC
and epinephrine has been reported occasionally. Beta-adrenergic blocking agents: Patients who
are receiving a beta-adrenergic blocking agent orally and TIMOPTIC
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 TIMOPTIC, 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
conduction time. 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. Clonidine: Oral
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. Injectable epinephrine: (See PRECAUTIONS, General,
Anaphylaxis.)<br/>Carcinogenesis, Mutagenesis, 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 (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, respectively, times the systemic exposure following
the maximum recommended human ophthalmic dose). In a subsequent study
in female mice, in which post-mortem examinations were limitedto
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 invivo (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 2is usually considered the criterion for a positive
Ames test. Reproduction 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.<br/>Pregnancy:<br/>Teratogenic Effects���Pregnancy Category C: Teratogenicity 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. TIMOPTIC
should be used during pregnancy only if the potential benefit justifies
the potential risk to the fetus.<br/>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 TIMOPTIC 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.<br/>Pediatric Use: Safety and effectiveness in pediatric patients have
not been established.<br/>Geriatric Use: No overall differences in safety or effectiveness
have been observed between elderly and younger patients.
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There have been reports of inadvertent overdosage
with TIMOPTIC 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). Overdosage has been reported
with Tablets BLOCADREN(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 block. An in vitro hemodialysis study, usingC 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.
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timolol maleate
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TIMOPTIC (Solution)
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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: BODY AS A WHOLE Headache, asthenia/fatigue,
and chest pain. CARDIOVASCULAR Bradycardia, arrhythmia, hypotension, hypertension, syncope, heart
block, cerebral vascular accident, cerebral ischemia, cardiac failure,
worsening of angina pectoris, palpitation, cardiac arrest, pulmonary
edema, edema, claudication, Raynaud's phenomenon, and cold hands and
feet. DIGESTIVE Nausea,
diarrhea, dyspepsia, anorexia, and dry mouth. IMMUNOLOGIC Systemic lupus erythematosus. NERVOUS SYSTEM/PSYCHIATRIC Dizziness,
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. SKIN Alopecia and psoriasiform rash or exacerbation of psoriasis. HYPERSENSITIVITY Signs and symptoms
of systemic allergic reactions, including anaphylaxis, angioedema,
urticaria, and localized and generalized rash. RESPIRATORY Bronchospasm (predominantly in
patients with pre-existing bronchospastic disease), respiratory failure,
dyspnea, nasal congestion, cough and upper respiratory infections. ENDOCRINE Masked symptoms of hypoglycemia
in diabetic patients . SPECIAL SENSES 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 ; and tinnitus. UROGENITAL Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie's
disease. The 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.
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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 .<br/>Cardiac Failure: Sympathetic stimulation may be essential for support
of the circulation in individuals with diminished myocardial contractility,
and its inhibition of 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, TIMOPTIC should be discontinued.<br/>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
is contraindicated [see CONTRAINDICATIONS]) should, in general, not receive beta-blockers, including TIMOPTIC.<br/>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.<br/>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.<br/>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 that might precipitate
a thyroid storm.
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TIMOPTIC Ophthalmic Solution is indicated in the
treatment of elevated intraocular pressure in patients with ocular
hypertension or open-angle glaucoma.
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TIMOPTIC
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