Istalol Information
Istalol (Timolol maleate) Description
Istalol (Timolol maleate) (timolol maleate ophthalmic solution) 0.5% is a non-selective beta-adrenergic receptor blocking agent. Its chemical name is (-)-1-(-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:
25º[α] in 1.0N HCl (C = 5%) = -12.2º (-11.7º to –12.5º) 405 nm
Its molecular formula is CHNOS-CHO and its structural formula is:
Timolol maleate has a molecular weight of 432.49. It is a white, odorless, crystalline powder which is soluble in water, methanol, and alcohol. Istalol (Timolol maleate) is stable at room temperature. Istalol (Timolol maleate) ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of timolol maleate in a single strength. It has a pH of 6.5-7.5 and an osmolality of 275-330 mOsm/kg.
Each mL of Istalol (Timolol maleate) contains 5 mg of timolol (6.8 mg of timolol maleate). Inactive ingredients: monobasic sodium phosphate monohydrate, potassium sorbate 0.47%, sodium chloride, sodium hydroxide, and purified water. Benzalkonium chloride 0.005% is added as preservative.
Istalol (Timolol maleate) Clinical Pharmacology
Timolol maleate is a beta and 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.
Istalol (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 nerve damage.
The onset of reduction in intraocular pressure following administration of Istalol (Timolol maleate) 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 Istalol (Timolol maleate) is well maintained.
The precise mechanism of the ocular hypotensive action of Istalol (Timolol maleate) 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.
Istalol (Timolol maleate) Indications And Usage
Istalol (Timolol maleate) ophthalmic solution is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Istalol (Timolol maleate) Contraindications
Istalol (Timolol maleate) is contraindicated in patients with (1) bronchial asthma; (2) a history of bronchial asthma; (3) severe chronic obstructive pulmonary disease (see ); (4) sinus bradycardia; (5) second or third degree atrioventricular block; (6) overt cardiac failure (see ); (7) cardiogenic shock; or (8) hypersensitivity to any component of this product.
Istalol (Timolol maleate) Warnings
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
Istalol (Timolol maleate) Precautions
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 Istalol (Timolol maleate) , 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, .)
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).
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. (See PRECAUTIONS, .)
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. (See .)
Patients should be advised that Istalol (Timolol maleate) 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 Istalol (Timolol maleate) administration.
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 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 (mouse) in the micronucleus test and cytogenetic assay (doses up to 800 mg/kg) and 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.
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.
Istalol (Timolol maleate) Adverse Reactions
The most frequently reported adverse experiences have been burning and stinging upon instillation in 38% of patients treated with Istalol (Timolol maleate) . Additional events reported with Istalol (Timolol maleate) at a frequency of 4 to 10% include: blurred vision, cataract, conjunctival injection, headache, hypertension, infection, itching and decreased visual acuity.
The following additional adverse experiences have been reported less frequently with ocular administration of this or other timolol maleate formulations:
BODY AS A WHOLEAsthenia/fatigue and chest pain.
CARDIOVASCULARBradycardia, arrhythmia, hypotension, 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/PSYCHIATRICDizziness, 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.
SKINAlopecia and psoriasiform rash or exacerbation of psoriasis.
HYPERSENSITIVITYSigns and symptoms of systemic allergic reactions, including angioedema, urticaria, and localized and generalized rash.
RESPIRATORYBronchospasm (predominantly in patients with pre-existing bronchospastic disease), respiratory failure, dyspnea, nasal congestion, cough and upper respiratory infections.
ENDOCRINEMasked symptoms of hypoglycemia in diabetic patients (see WARNINGS).
SPECIAL SENSESSigns 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, ); 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: Erythematous rash, fever combined with aching and sore throat, laryngospasm with respiratory distress; Extremity pain, decreased exercise tolerance, weight loss; Worsening of arterial insufficiency, vasodilatation; Gastrointestinal pain, hepatomegaly, vomiting, mesenteric arterial thrombosis, ischemic colitis; Nonthrombocytopenic purpura; thrombocytopenic purpura, agranulocytosis; Hyperglycemia, hypoglycemia; Pruritus, skin irritation, increased pigmentation, sweating; Arthralgia; 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; Rales, bronchial obstruction; Urination difficulties.
Istalol (Timolol maleate) Overdosage
There have been reports of inadvertent overdosage with Istalol (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 ).
An hemodialysis study, using C 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.
Istalol (Timolol maleate) Dosage And Administration
Istalol (Timolol maleate) ophthalmic solution is available in a concentration of 0.5 percent. The starting dose is one drop of 0.5 percent Istalol (Timolol maleate) in the affected eye(s) once a day in the AM. If the patient's intraocular pressure is 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, .)
Istalol (Timolol maleate) How Supplied
Sterile Ophthalmic Solution Istalol (Timolol maleate) is a clear, colorless to light yellow solution. Istalol (Timolol maleate) Ophthalmic Solution, 0.5% supplied in a white LDPE bottle with 15 mm LDPE yellow cap and 15 mm LDPE white dropper tip as follows:
NDC 67425-003-50 5 mL in 10 mL container
NDC 67425-003-12 2.5 mL in 7.5 mL container
Istalol (Timolol maleate)
