BETIMOL- timolol solution

United States - English - NLM (National Library of Medicine)

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Active ingredient:
timolol (UNII: 817W3C6175) (timolol - UNII:817W3C6175)
Available from:
Vistakon Pharmaceuticals LLC
INN (International Name):
timolol
Composition:
timolol 2.5 mg in 1 mL
Administration route:
OPHTHALMIC
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Betimol® is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Betimol® is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia, second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.
Product summary:
Betimol® (timolol ophthalmic solution) is a clear, colorless solution. Betimol® 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows: Betimol® 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows: Rx Only Store between 15-25°C (59-77°F). Do not freeze. Protect from light.
Authorization status:
New Drug Application
Authorization number:
68669-522-05, 68669-525-05, 68669-525-10, 68669-525-15, 68669-525-99

BETIMOL- timolol solution

Vistakon Pharmaceuticals LLC

----------

BETIMOL (timolol ophthalmic solution)

0.25%, 0.5%

DESCRIPTION

Betimol

(timolol ophthalmic solution), 0.25% and 0.5%, is a non-selective beta-adrenergic antagonist

for ophthalmic use. The chemical name of the active ingredient is (S)-1-[(1,1-dimethylethyl)amino]-3-

[(4-(4-morpholinyl)-1,2,5-thiadiazol-3-yl]oxy]-2-propanol. Timolol hemihydrate is the levo isomer.

Specific rotation is [α]

=-16° (C=10% as the hemihydrate form in 1N HCl).

The molecular formula of timolol is Formula C

H N O S and its structural formula is:

Timolol (as the hemihydrate) is a white, odorless, crystalline powder which is slightly soluble in water

and freely soluble in ethanol. Timolol hemihydrate is stable at room temperature.

Betimol

is a clear, colorless, isotonic, sterile, microbiologically preserved phosphate buffered

aqueous solution.

It is supplied in two dosage strengths, 0.25% and 0.5%.

Each mL of Betimol

0.25% contains 2.56 mg of timolol hemihydrate equivalent to 2.5 mg Timolol.

Each mL of Betimol

0.5% contains 5.12 mg of timolol hemihydrate equivalent to 5.0 mg timolol.

Inactive ingredients: monosodium and disodium phosphate dihydrate to adjust pH (6.5 - 7.5) and water

for injection, benzalkonium chloride 0.01% added as preservative.

The osmolality of Betimol

is 260 to 320 mOsmol/kg.

CLINICAL PHARMACOLOGY

Timolol is a non-selective beta-adrenergic antagonist.

It blocks both beta -and beta -adrenergic receptors. Timolol does not have significant intrinsic

sympathomimetic activity, local anesthetic (membrane-stabilizing) or direct myocardial depressant

activity.

Timolol, when applied topically in the eye, reduces normal and elevated intraocular pressure (IOP)

®

405nm

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 IOP, the greater the likelihood

of glaucomatous visual field loss and optic nerve damage. The predominant mechanism of ocular

hypotensive action of topical beta-adrenergic blocking agents is likely due to a reduction in aqueous

humor production.

In general, beta-adrenergic blocking agents reduce cardiac output both in healthy subjects and patients

with heart diseases. In patients with severe impairment of myocardial function, beta-adrenergic receptor

blocking agents may inhibit sympathetic stimulatory effect necessary to maintain adequate cardiac

function. In the bronchi and bronchioles, beta-adrenergic receptor blockade may also increase airway

resistance because of unopposed parasympathetic activity.

Pharmacokinetics

When given orally, timolol is well absorbed and undergoes considerable first pass metabolism. Timolol

and its metabolites are primarily excreted in the urine. The half-life of timolol in plasma is

approximately 4 hours.

Clinical Studies

In two controlled multicenter studies in the U.S., Betimol

0.25% and 0.5% were compared with

respective timolol maleate eyedrops. In these studies, the efficacy and safety profile of Betimol

similar to that of timolol maleate.

INDICATIONS AND USAGE

Betimol

is indicated in the treatment of elevated intraocular pressure in patients with ocular

hypertension or open-angle glaucoma.

CONTRAINDICATIONS

Betimol

is contraindicated in patients with overt heart failure, cardiogenic shock, sinus bradycardia,

second- or third-degree atrioventricular block, bronchial asthma or history of bronchial asthma, or

severe chronic obstructive pulmonary disease, or hypersensitivity to any component of this product.

WARNINGS

As with other topically applied ophthalmic drugs, Betimol

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 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 topical administration of beta-adrenergic blocking agents.

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 cardiac 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. Betimol

should be

discontinued at the first sign or symptom of cardiac failure.

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 which are contraindications) should in general not receive beta-

blocking agents.

Major Surgery

The necessity or desirability of withdrawal of beta-adrenergic blocking agents prior to a 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 receptor blocking agents is recommended. If necessary during surgery, the effects

of beta-adrenergic blocking agents may be reversed by sufficient doses of beta-adrenergic agonists.

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.

Thyrotoxicos is

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

Because of the 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 develop following initiation of therapy with

Betimol

, 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. (See

PRECAUTIONS, Information for Patients.)

Muscle Weakness

Beta-adrenergic blockade has been reported to potentiate muscle weakness consistent with certain

myasthenic symptoms (e.g. dipIopia, ptosis, and generalized weakness). Beta-adrenergic blocking agents

have been reported rarely to increase muscle weakness in some patients with myasthenia gravis or

myasthenic symptoms.

In angle-closure glaucoma, the goal of the treatment is to reopen the angle. This requires constricting

the pupil. Betimol

has no effect on the pupil. Therefore, if timolol is used in angle-closure glaucoma,

it should always be combined with a miotic and not used alone.

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.

The preservative benzalkonium chloride may be absorbed by soft contact lenses. Patients who wear soft

contact lenses should wait 5 minutes after instilling Betimol

before they insert their lenses.

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 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 PRECAUTIONS, General.)

Patients requiring concomitant topical ophthalmic medications should be instructed to administer these at

least 5 minutes apart.

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.)

Drug Interactions

Beta-adrenergic blocking agents

Patients who are receiving a beta-adrenergic blocking agent orally and Betimol

should be observed

for a potential additive effect either on the intraocular pressure or on the known systemic effects of

beta-blockade.

Patients should not usually receive two topical ophthalmic beta-adrenergic blocking agents

concurrently.

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 produce vertigo, syncope, or

postural hypotension.

Calcium antagonists

Caution should be used in the co-administration of beta-adrenergic blocking agents and oral or

intravenous calcium antagonists, because of possible atrioventricular conduction disturbances, left

ventricular failure, and hypotension. In patients with impaired cardiac function, co-administration should

be avoided.

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.

Injectable Epinephrine

(See PRECAUTIONS, General, Anaphylaxis.)

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenicity of timolol (as the maleate) has been studied in mice and rats. In a two-year study orally

administrated timolol maleate (300mg/kg/day) (approximately 42,000 times the systemic exposure

following the maximum recommended human ophthalmic dose) in male rats caused a significant increase

in the incidence of adrenal pheochromocytomas; the lower doses, 25 mg or 100 mg/kg daily did not

cause any changes.

In a life span study in mice the overall incidence of neoplasms was significantly increased in female

mice at 500 mg/kg/day (approximately 71,000 times the systemic exposure following the maximum

recommended human ophthalmic dose). Furthermore, significant increases were observed in the

incidences of benign and malignant pulmonary tumors, benign uterine polyps, as well as mammary

adenocarcinomas. These changes were not seen at the daily dose level of 5 or 50 mg/kg (approximately

700 or 7,000, respectively, times the systemic exposure following the maximum recommended human

ophthalmic dose). For comparison, the maximum recommended human oral dose of timolol maleate is 1

mg/kg/day.

Mutagenic potential of timolol was evaluated in vivo in the micronucleus test and cytogenetic assay and

in vitro in the neoplastic cell transformation assay and Ames test. In the bacterial mutagenicity test (Ames

test) high concentrations of timolol maleate (5000 and 10,000 g/plate) statistically significantly

increased the number of revertants in Salmonella typhimurium TA100, but not in the other three strains

tested. However, no consistent dose-response was observed nor did the number of revertants reach the

double of the control value, which is regarded as one of the criteria for a positive result in the Ames

test. In vivo genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and in vitro the

neoplastic cell transformation assay were negative up to dose levels of 800 mg/kg and 100 g/mL,

respectively.

No adverse effects on male and female fertility were reported in rats at Timolol oral doses of up to 150

mg/kg/day (21,000 times the systemic exposure following the maximum recommended human

ophthalmic dose).

Pregnancy Teratogenic effects

Category C

Teratogenicity of timolol (as the maleate) after oral administration was studied in mice and rabbits. No

fetal malformations were reported in mice or rabbits at a daily oral dose of 50 mg/kg (7,000 times the

systemic exposure following the maximum recommended human ophthalmic dose). 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. Betimol

should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing mothers

Because of the potential for serious adverse reactions in nursing infants from timolol, 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 efficacy in pediatric patients have not been established.

ADVERSE REACTIONS

The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was

comparable between Betimol

and timolol maleate (approximately one in eight patients).

The following adverse events were associated with use of Betimol

in frequencies of more than 5% in

two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5%

Betimol

OCULAR:

Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection,

and headache.

BODY AS A WHOLE:

Headache.

The following side effects were reported in frequencies of 1 to 5%:

OCULAR:

Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis,

blepharitis and cataract.

BODY AS A WHOLE:

Allergic reaction, asthenia, common cold and pain in extremities.

CARDIOVASCULAR:

Hypertension.

DIGESTIVE:

Nausea.

METABOLlC/NUTRITIONAL:

Peripheral edema.

NERVOUS SYSTEM/PSYCHIATRY:

Dizziness and dry mouth.

RESPIRATORY:

Respiratory infection and sinusitis.

In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:

OCULAR:

Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive

changes, diplopia and retinal vascular disorder.

BODY AS A WHOLE:

Chest pain.

CARDIOVASCULAR:

Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident,

cerebral ischemia, cardiac failure and cardiac arrest.

DIGESTIVE:

Diarrhea.

ENDOCRINE:

Masked symptoms of hypoglycemia in insulin dependent diabetics (See WARNINGS).

NERVOUS SYSTEM/PSYCHIATRY:

Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.

RESPIRATORY:

Dyspnea, bronchospasm, respiratory failure and nasal congestion.

SKIN:

AIOPecia, hypersensitivity including localized and generalized rash, urticaria.

OVERDOSAGE

No information is available on overdosage with Betimol

. Symptoms that might be expected with an

overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia,

and acute cardiac failure.

DOSAGE AND ADMINISTRATION

Betimol

Ophthalmic Solution is available in concentrations of 0.25 and 0.5 percent. The usual starting

dose is one drop of 0.25 percent Betimol

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.

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.

Since in some patients the pressure-lowering response to Betimol

may require a few weeks to

stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks

of treatment with Betimol

Dosages above one drop of 0.5 percent Betimol

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 pilocarpine and other miotics, and/or

epinephrine, and/or systemically administered carbonic anhydrase inhibitors, such as acetazolamide, can

be instituted.

HOW SUPPLIED

Betimol

(timolol ophthalmic solution) is a clear, colorless solution.

Betimol

0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled

drop tip as follows:

NDC 68669-522-05

5.0mL

fill in 5 cc container

NDC 68669-522-10

10mL

fill in 11 cc container

NDC 68669-522-15

15mL

fill in 15 cc container

Betimol

0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled

drop tip as follows:

NDC 68669-525-05

5.0mL

fill in 5 cc container

NDC 68669-525-10

10mL

fill in 11 cc contalner

NDC 68669-525-15

15mL

fill in 15 cc container

Rx Only

STORAGE

Store between 15-25°C (59-77°F). Do not freeze. Protect from light.

MARKETED BY:

VISTAKON Pharmaceuticals, LLC

Jacksonville, FL 32256 USA

MANUFACTURED BY:

Santen Oy, P.O. Box 33

FIN-33721 Tampere, Finland

November 2006 Version

3220660/5

PRINCIPAL DISPLAY PANEL - 0.25% Carton

NDC 68669-522-05

BETIMOL

(TIMOLOL OPHTHALMIC

SOLUTION) 0.25%

Timolol equivalent (timolol

hemihydrate 2.56 mg/mL)

Rx Only

5 mL

VISTAKON

PHARMACEUTICALS, LLC

®

®

PRINCIPAL DISPLAY PANEL - 5 mL Bottle Label

NDC 68669-525-05

BETIMOL

(TIMOLOL OPHTHALMIC

SOLUTION) 0.5%

Timolol equivalent (timolol

hemihydrate 5.12 mg/mL)

5 mL

VISTAKON

PHARMACEUTICALS, LLC

®

®

BETIMOL

timolol solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 6 6 9 -522

Route of Administration

OPHTHALMIC

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

timo lo l (UNII: 8 17W3C6 175) (timo lo l - UNII:8 17W3C6 175)

timo lo l

2.5 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

benza lko nium chlo ride (UNII: F5UM2KM3W7)

0 .1 mg in 1 mL

so dium pho spha te, mo no ba sic, dihydra te (UNII: 5QWK6 6 59 56 )

10 .53 mg in 1 mL

so dium pho spha te, diba sic, dihydra te (UNII: 9 4255I6 E2T)

12.0 1 mg in 1 mL

wa ter (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 6 6 9 -522-0 5

5 mL in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 439

10 /0 1/20 0 0

Vistakon Pharmaceuticals LLC

BETIMOL

timolol solution

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 6 6 9 -525

Route of Administration

OPHTHALMIC

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

timo lo l (UNII: 8 17W3C6 175) (timo lo l - UNII:8 17W3C6 175)

timo lo l

5 mg in 1 mL

Inactive Ingredients

Ingredient Name

Stre ng th

benza lko nium chlo ride (UNII: F5UM2KM3W7)

0 .1 mg in 1 mL

so dium pho spha te, mo no ba sic, dihydra te (UNII: 5QWK6 6 59 56 )

10 .53 mg in 1 mL

so dium pho spha te, diba sic, dihydra te (UNII: 9 4255I6 E2T)

12.0 1 mg in 1 mL

wa ter (UNII: 0 59 QF0 KO0 R)

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 6 6 9 -525-9 9

2.5 mL in 1 BOTTLE

2

NDC:6 8 6 6 9 -525-0 5

5 mL in 1 BOTTLE

3

NDC:6 8 6 6 9 -525-10

10 mL in 1 BOTTLE

4

NDC:6 8 6 6 9 -525-15

15 mL in 1 BOTTLE

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

NDA0 20 439

10 /0 1/20 0 0

Labeler -

Vistakon Pharmaceuticals LLC (004060273)

Revised: 3/2010

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