Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1310
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TIMOPTIC-XE (Solution, Gel Forming, Extended Release)
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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. Other topically applied ophthalmic medications
should be administered at least 10 minutes before TIMOPTIC���XE. TIMOPTIC���XE Sterile Ophthalmic Gel Forming Solution
is available in concentrations of 0.25% and 0.5%. The dose is one
drop of TIMOPTIC���XE (either 0.25% or 0.5%) in the affected
eye(s) once a day. Because in some patients
the pressure-lowering response to TIMOPTIC���XE may require a
few weeks to stabilize, evaluation should include a determination
of intraocular pressure after approximately 4 weeks of treatment with
TIMOPTIC���XE. Dosages higher than one
drop of 0.5% TIMOPTIC���XE once a day have not been studied.
If the patient's intraocular pressure is still not at a satisfactory
level on this regimen, concomitant therapy can be considered. The
concomitant use of two topical beta-adrenergic blocking agents is
not recommended. When patients have been switched from therapy
with TIMOPTIC administered twice daily to TIMOPTIC���XE administered
once daily, the ocular hypotensive effect has remained consistent.
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TIMOPTIC���XE(timolol maleate ophthalmic gel forming 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: 25��[��] in
1.0N HCl (C = 5%) =���12.2��(���11.7��to���12.5��).405
nm 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���XE
Sterile Ophthalmic Gel Forming Solution is supplied as a sterile,
isotonic, buffered, aqueous solution of timolol maleate in two dosage
strengths. The pH of the solution is approximately 7.0, and the osmolarity
is 260-330 mOsm. Each mL of TIMOPTIC���XE 0.25% contains 2.5
mg of timolol (3.4 mg of timolol maleate). Each mL of TIMOPTIC���XE
0.5% contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive
ingredients: GELRITE gellan gum, tromethamine, mannitol, and water
for injection. Preservative: benzododecinium bromide 0.012%. GELRITE is a purified anionic heteropolysaccharide derived
from gellan gum. An aqueous solution of GELRITE, in the presence of
a cation, has the ability to gel. Upon contact with the precorneal
tear film, TIMOPTIC���XE forms a gel that is subsequently removed
by the flow of tears.
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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. TIMOPTIC���XE, 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 and optic nerve damage. The
precise mechanism of the ocular hypotensive action of TIMOPTIC���XE
is not clearly established at this time. Tonography and fluorophotometry
studies of TIMOPTIC(timolol maleate ophthalmic solution) 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. 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.<br/>Pharmacokinetics: In a study of plasma drug concentration in six subjects,
the systemic exposure to timolol was determined following once daily
administration of TIMOPTIC���XE 0.5% in the morning. The mean
peak plasma concentration following this morning dose was 0.28 ng/mL.<br/>Clinical Studies: In controlled, double-masked, multicenter clinical
studies, comparing TIMOPTIC���XE 0.25% to TIMOPTIC 0.25% and
TIMOPTIC���XE 0.5% to TIMOPTIC 0.5%, TIMOPTIC���XE administered
once a day was shown to be equally effective in lowering intraocular
pressure as the equivalent concentration of TIMOPTIC administered
twice a day. The effect of timolol in lowering intraocular pressure
was evident for 24 hours with a single dose of TIMOPTIC���XE.
Repeated observations over a period of six months indicate that the
intraocular pressure-lowering effect of TIMOPTIC���XE was consistent.
The results from the largest U.S. and international clinical trials
comparing TIMOPTIC���XE 0.5% to TIMOPTIC 0.5% are shown in Figure
1. TIMOPTIC���XE administered once daily had a safety
profile similar to that of an equivalent concentration of TIMOPTIC
administered twice daily. Due to the physical characteristics of the
formulation, there was a higher incidence of transient blurred vision
in patients administered TIMOPTIC���XE. A slight reduction in
resting heart rate was observed in some patients receiving TIMOPTIC���XE
0.5% (mean reduction 24 hours post-dose 0.8 beats/minute, mean reduction
2 hours post-dose 3.8 beats/minute). TIMOPTIC���XE has not been studied in patients wearing
contact lenses.
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TIMOPTIC���XE 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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TIMOPTIC���XE Sterile Ophthalmic Gel Forming
Solution is a colorless to nearly colorless, slightly opalescent,
and slightly viscous solution. No. 3557���TIMOPTIC���XE Sterile Ophthalmic Gel Forming Solution, 0.25%
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 0006-3557-35, 5 mL in a 7.5 mL capacity bottle. No. 3558���TIMOPTIC���XE Sterile Ophthalmic
Gel Forming 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 0006-3558-35,
5 mL in a 7.5 mL capacity bottle.<br/>Storage: Store at 15-30��C (59-86��F). AVOID FREEZING. Protect from light. Manuf. for:MERCK&CO., Inc., Whitehouse Station, NJ 08889, USA By: Laboratories Merck Sharp&Dohme-Chibret63963
Clermont-Ferrand Cedex 9, France Issued September
2005 325A-07/05 514042Z 9611903
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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���XE, 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 may require constricting
the pupil. Timolol maleate has little or no effect on the pupil. TIMOPTIC���XE
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
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 TIMOPTIC���XE. 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. 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.<br/>Drug Interactions: Beta-adrenergic blocking
agents: Patients who are receiving a beta-adrenergic blocking
agent orally and TIMOPTIC���XE 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���XE, and oral or intravenous calcium antagonists
because of possible atrioventricular conduction disturbances, left
ventricular failure, or 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:<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 studyin 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 oral 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) 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 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, 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. 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:<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���XE 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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No data are available in regard to human overdosage
with or accidental oral ingestion of TIMOPTIC���XE. 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 . 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-XE (Solution, Gel Forming, Extended Release)
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In clinical trials, transient blurred vision upon
instillation of the drop was reported in approximately one in three
patients (lasting from 30 seconds to 5 minutes). Less than 1% of patients
discontinued from the studies due to blurred vision. The frequency
of patients reporting burning and stinging upon instillation was comparable
between TIMOPTIC���XE and TIMOPTIC (approximately one in eight
patients). Adverse experiences reported in
1���5% of patients were: Ocular:Pain,
conjunctivitis, discharge (e.g., crusting), foreign body sensation,
itching and tearing; Systemic:Headache,
dizziness, and upper respiratory infections. The following additional adverse experiences have been reported with
the ocular administration of this or other timolol maleate formulations: BODY AS A WHOLEAsthenia/fatigue, and chest pain. CARDIOVASCULARBradycardia, 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. DIGESTIVENausea,
diarrhea, dyspepsia, anorexia, and dry mouth. IMMUNOLOGICSystemic lupus erythematosus. NERVOUS SYSTEM/PSYCHIATRICIncrease 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. SKINAlopecia and psoriasiform
rash or exacerbation of psoriasis. HYPERSENSITIVITYSigns and symptoms of systemic allergic reactions including anaphylaxis,
angioedema, urticaria, localized and generalized rash. RESPIRATORYBronchospasm (predominantly in patients
with pre-existing bronchospastic disease), respiratory failure, dyspnea,
nasal congestion, and cough. ENDOCRINEMasked
symptoms of hypoglycemia in diabetic patients . SPECIAL
SENSESSigns and symptoms of ocular irritation including blepharitis,
keratitis, 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. UROGENITALRetroperitoneal 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 ophthalmic 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 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, TIMOPTIC���XE 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���XE
is contraindicated [see CONTRAINDICATIONS]) should, in
general, not receive beta-blockers, including TIMOPTIC���XE.<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���XE Sterile Ophthalmic Gel Forming
Solution is indicated in the treatment of elevated intraocular pressure
in patients with ocular hypertension or open-angle glaucoma.
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TIMOPTIC-XE
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