Timoptic Information
Timoptic (Timolol) Description
Timolol maleate 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:
25°[α] in 1.0N HCl (C = 5%) = –12.2° (–11.7° to –12.5°). 405 nm
Its molecular formula is CHNOS•CHO and 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. Timolol maleate is stable at room temperature.
Timolol maleate ophthalmic solution is supplied in two formulations: Ophthalmic Solution Timoptic (Timolol) (timolol maleate ophthalmic solution), which contains the preservative benzalkonium chloride; and Ophthalmic Solution Timoptic (Timolol) (timolol maleate ophthalmic solution), the preservative-free formulation.
Preservative-free Ophthalmic Solution Timoptic (Timolol) is supplied in OCUDOSE, a unit dose container, as a sterile, isotonic, buffered, aqueous solution of timolol maleate in two dosage strengths: Each mL of Preservative-free Timoptic (Timolol) in OCUDOSE 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 252-328 mOsm. Each mL of Preservative-free Timoptic (Timolol) in OCUDOSE 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.
Timoptic (Timolol) 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.
Timoptic (Timolol) (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 Timoptic (Timolol) (timolol maleate ophthalmic solution) 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 (Timolol) (timolol maleate ophthalmic solution) is well maintained.
The precise mechanism of the ocular hypotensive action of Timoptic (Timolol) (timolol maleate ophthalmic solution) 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.
In controlled multiclinic studies in patients with untreated intraocular pressures of 22 mmHg or greater, Timoptic (Timolol) (timolol maleate ophthalmic solution) 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 (Timolol) (timolol maleate ophthalmic solution) 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 (Timolol) (timolol maleate ophthalmic solution) (mean reduction 2.9 beats/minute standard deviation 10.2) was observed.
Timoptic (Timolol) Indications And Usage
Preservative-free Timoptic (Timolol) in OCUDOSE is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma.
Preservative-free Timoptic (Timolol) in OCUDOSE may be used when a patient is sensitive to the preservative in Timoptic (Timolol) (timolol maleate ophthalmic solution), benzalkonium chloride, or when use of a preservative-free topical medication is advisable.
Timoptic (Timolol) Contraindications
Preservative-free Timoptic (Timolol) in OCUDOSE 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.
Timoptic (Timolol) Warnings
As with many topically applied ophthalmic drugs, this drug is absorbed systemically.
Timoptic (Timolol) 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 Preservative-free Timoptic (Timolol) in OCUDOSE, alternative therapy should be considered.
Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g. timolol).
Angle-closure glaucoma:
Anaphylaxis:
Muscle Weakness:
Patients should be instructed about the use of Preservative-free Timoptic (Timolol) in OCUDOSE.
Since sterility cannot be maintained after the individual unit is opened, patients should be instructed to use the product immediately after opening, and to discard the individual unit and any remaining contents immediately after use.
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 .)
Although Timoptic (Timolol) (timolol maleate ophthalmic solution) used alone has little or no effect on pupil size, mydriasis resulting from concomitant therapy with Timoptic (Timolol) (timolol maleate ophthalmic solution) and epinephrine has been reported occasionally.
Beta-adrenergic blocking agents:
Calcium antagonists:
Catecholamine-depleting drugs:
Digitalis and calcium antagonists:
CYP2D6 inhibitors:
Clonidine:
Injectable epinephrine:
PRECAUTIONS, General, Anaphylaxis
In a two-year oral 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 times, respectively, 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.
Timoptic (Timolol) Adverse Reactions
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 (see ).
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 (see ); 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: 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.
Timoptic (Timolol) Overdosage
There have been reports of inadvertent overdosage with Ophthalmic Solution Timoptic (Timolol) (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 ).
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 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.
Timoptic (Timolol) Dosage And Administration
Preservative-free Timoptic (Timolol) in OCUDOSE is a sterile solution that does not contain a preservative. The solution from one individual unit is to be used immediately after opening for administration to one or both eyes. Since sterility cannot be guaranteed after the individual unit is opened, the remaining contents should be discarded immediately after administration.
Preservative-free Timoptic (Timolol) in OCUDOSE is available in concentrations of 0.25 and 0.5 percent. The usual starting dose is one drop of 0.25 percent Preservative-free Timoptic (Timolol) in OCUDOSE in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual container to obtain a single drop of solution. 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) administered twice a day.
Since in some patients the pressure-lowering response to Preservative-free Timoptic (Timolol) in OCUDOSE may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with Preservative-free Timoptic (Timolol) in OCUDOSE.
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 (Timolol) (timolol maleate ophthalmic solution) 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 taking into consideration that the preparation(s) used concomitantly may contain one or more preservatives. The concomitant use of two topical beta-adrenergic blocking agents is not recommended. (See .)
Timoptic (Timolol) How Supplied
Preservative-free Sterile Ophthalmic Solution Timoptic (Timolol) in OCUDOSE is a clear, colorless to light yellow solution.
No. 9689 — Preservative-free Timoptic (Timolol) , 0.25% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:
No. 9690 — Preservative-free Timoptic (Timolol) , 0.5% timolol equivalent, is supplied in OCUDOSE, a clear low density polyethylene unit dose container. Each individual unit contains 0.2 mL of solution, and is available in a foil laminate overwrapped pouch as follows:
