Betimol Information
Betimol (Timolol) Description
Betimol (Timolol) (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 CHNOS 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 (Timolol) 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 (Timolol) 0.25% contains 2.56 mg of timolol hemihydrate equivalent to 2.5 mg Timolol.
Each mL of Betimol (Timolol) 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 (Timolol) is 260 to 320 mOsmol/kg.
Betimol (Timolol) 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) 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.
Betimol (Timolol) Indications And Usage
Betimol (Timolol) is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Betimol (Timolol) Contraindications
Betimol (Timolol) 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.
Betimol (Timolol) Warnings
As with other topically applied ophthalmic drugs, Betimol (Timolol) 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.
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 (Timolol) should be discontinued at the first sign or symptom of cardiac failure.
Betimol (Timolol) Precautions
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 (Timolol) , 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 .)
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 .)
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 .)
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 the micronucleus test and cytogenetic assay and 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 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. genotoxicity tests (the mouse micronucleus test and cytogenetic assay) and 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).
Betimol (Timolol) Adverse Reactions
The most frequently reported ocular event in clinical trials was burning/stinging on instillation and was comparable between Betimol (Timolol) and timolol maleate (approximately one in eight patients).
The following adverse events were associated with use of Betimol (Timolol) in frequencies of more than 5% in two controlled, double-masked clinical studies in which 184 patients received 0.25% or 0.5% Betimol (Timolol) :
Dry eyes, itching, foreign body sensation, discomfort in the eye, eyelid erythema, conjunctival injection, and headache.
Headache.
The following side effects were reported in frequencies of 1 to 5%:
Eye pain, epiphora, photophobia, blurred or abnormal vision, corneal fluorescein staining, keratitis, blepharitis and cataract.
Allergic reaction, asthenia, common cold and pain in extremities.
Hypertension.
Nausea.
Peripheral edema.
Dizziness and dry mouth.
Respiratory infection and sinusitis.
In addition, the following adverse reactions have been reported with ophthalmic use of beta blockers:
Conjunctivitis, blepharoptosis, decreased corneal sensitivity, visual disturbances including refractive changes, diplopia and retinal vascular disorder.
Chest pain.
Arrhythmia, palpitation, bradycardia, hypotension, syncope, heart block, cerebral vascular accident, cerebral ischemia, cardiac failure and cardiac arrest.
Diarrhea.
Masked symptoms of hypoglycemia in insulin dependent diabetics (See ).
Depression, impotence, increase in signs and symptoms of myasthenia gravis and paresthesia.
Dyspnea, bronchospasm, respiratory failure and nasal congestion.
AIOPecia, hypersensitivity including localized and generalized rash, urticaria.
Betimol (Timolol) Overdosage
No information is available on overdosage with Betimol (Timolol) . Symptoms that might be expected with an overdose of a beta-adrenergic receptor blocking agent are bronchospasm, hypotension, bradycardia, and acute cardiac failure.
Betimol (Timolol) Dosage And Administration
Betimol (Timolol) 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 (Timolol) 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 (Timolol) may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Betimol (Timolol) .
Dosages above one drop of 0.5 percent Betimol (Timolol) 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.
Betimol (Timolol) How Supplied
Betimol (Timolol) (timolol ophthalmic solution) is a clear, colorless solution.
Betimol (Timolol) 0.25% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:
Betimol (Timolol) 0.5% is supplied in a white, opaque, plastic, ophthalmic dispenser bottle with a controlled drop tip as follows:
Rx Only
Betimol (Timolol)
Betimol (Timolol) Principal Display Panel - .% Carton
Betimol (Timolol) Principal Display Panel - Ml Bottle Label
