TIMOLOL: 7,450 Adverse Event Reports & Safety Profile
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Drug Class: Adrenergic beta-Antagonists [MoA] · Route: OPHTHALMIC · Manufacturer: Bausch & Lomb Incorporated · FDA Application: 018017 · HUMAN PRESCRIPTION DRUG · FDA Label: Available
First Report: 1979 · Latest Report: 20250921
What Are the Most Common TIMOLOL Side Effects?
All TIMOLOL Side Effects by Frequency
| Side Effect | Reports | % of Total | Deaths | Hosp. |
|---|---|---|---|---|
| Treatment failure | 3,690 | 49.5% | 0 | 1 |
| Drug ineffective | 684 | 9.2% | 9 | 48 |
| Hypersensitivity | 526 | 7.1% | 0 | 13 |
| Eye irritation | 421 | 5.7% | 0 | 12 |
| Ocular hyperaemia | 262 | 3.5% | 0 | 8 |
| Intraocular pressure increased | 231 | 3.1% | 0 | 14 |
| Eye pain | 229 | 3.1% | 0 | 9 |
| Eye pruritus | 228 | 3.1% | 0 | 2 |
| Vision blurred | 212 | 2.9% | 0 | 3 |
| Dizziness | 201 | 2.7% | 0 | 27 |
| Drug hypersensitivity | 161 | 2.2% | 0 | 7 |
| Dyspnoea | 135 | 1.8% | 1 | 55 |
| Visual impairment | 124 | 1.7% | 0 | 4 |
| Fatigue | 115 | 1.5% | 0 | 5 |
| Bradycardia | 111 | 1.5% | 0 | 81 |
| Lacrimation increased | 111 | 1.5% | 0 | 3 |
| Product quality issue | 106 | 1.4% | 0 | 3 |
| Dry eye | 103 | 1.4% | 0 | 3 |
| Glaucoma | 100 | 1.3% | 0 | 10 |
| Off label use | 99 | 1.3% | 1 | 22 |
Who Reports TIMOLOL Side Effects? Age & Gender Data
Gender: 61.9% female, 38.1% male. Average age: 67.1 years. Most reports from: US. View detailed demographics →
Is TIMOLOL Getting Safer? Reports by Year
| Year | Reports | Deaths | Hosp. |
|---|---|---|---|
| 2000 | 5 | 0 | 2 |
| 2001 | 1 | 0 | 0 |
| 2002 | 3 | 0 | 0 |
| 2003 | 10 | 0 | 0 |
| 2004 | 5 | 0 | 2 |
| 2005 | 6 | 0 | 3 |
| 2006 | 11 | 0 | 5 |
| 2007 | 6 | 0 | 2 |
| 2008 | 9 | 0 | 1 |
| 2009 | 11 | 0 | 1 |
| 2010 | 25 | 3 | 6 |
| 2011 | 7 | 0 | 2 |
| 2012 | 21 | 0 | 7 |
| 2013 | 46 | 0 | 5 |
| 2014 | 75 | 0 | 16 |
| 2015 | 123 | 5 | 21 |
| 2016 | 135 | 0 | 17 |
| 2017 | 83 | 0 | 12 |
| 2018 | 129 | 1 | 43 |
| 2019 | 114 | 1 | 12 |
| 2020 | 128 | 14 | 11 |
| 2021 | 82 | 4 | 15 |
| 2022 | 65 | 2 | 2 |
| 2023 | 80 | 3 | 17 |
| 2024 | 65 | 0 | 2 |
| 2025 | 36 | 0 | 11 |
What Is TIMOLOL Used For?
| Indication | Reports |
|---|---|
| Product used for unknown indication | 5,043 |
| Glaucoma | 1,142 |
| Intraocular pressure increased | 299 |
| Open angle glaucoma | 128 |
| Ocular hypertension | 66 |
| Intraocular pressure test abnormal | 43 |
| Intraocular pressure test | 32 |
| Infantile haemangioma | 25 |
| Angle closure glaucoma | 24 |
| Developmental glaucoma | 16 |
TIMOLOL vs Alternatives: Which Is Safer?
Other Drugs in Same Class: Adrenergic beta-Antagonists [MoA]
Official FDA Label for TIMOLOL
Official prescribing information from the FDA-approved drug label.
Drug Description
DESCRIPTION Timolol Maleate ophthalmic 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 nominal optical rotation of Timolol Maleate is: Its molecular formula is C 13 H 24 N 4 O 3 S
- C 4 H 4 O 4 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 ophthalmic solution is stable at room temperature.
Timolol
Maleate ophthalmic solution is supplied as a sterile, isotonic, buffered, aqueous solution of Timolol Maleate in two dosage strengths: Each mL, for ophthalmic administration, of 0.25% solution contains 2.5 mg of timolol (3.4 mg of Timolol Maleate). The pH of the solution is approximately 7.0. Each mL, for ophthalmic administration, of 0.5% solution contains 5 mg of timolol (6.8 mg of Timolol Maleate). Inactive ingredients: monobasic and dibasic sodium phosphate; hydrochloric acid and/or sodium hydroxide to adjust pH; and purified water. Benzalkonium chloride 0.01% is added as preservative.
Timolol
Maleate ophthalmic 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 nominal optical rotation of Timolol Maleate is: The structural formula for 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 ophthalmic solution is stable at room temperature.
FDA Approved Uses (Indications)
INDICATIONS AND USAGE Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial is indicated in the treatment of elevated intraocular pressure in patients with ocular hypertension or open-angle glaucoma. Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial may be used when a patient is sensitive to the preservative in timolol maleate ophthalmic solution USP, benzalkonium chloride, or when use of a preservative-free topical medication is advisable.
Dosage & Administration
DOSAGE AND ADMINISTRATION Preservative-free timolol maleate ophthalmic solution USP in the unit dose vial 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 timolol maleate ophthalmic solution in the unit dose vial is available in concentrations of 0.25% and 0.5%. The usual starting dose is one drop of 0.25% preservative-free timolol maleate ophthalmic solution in the unit dose vial in the affected eye(s) administered twice a day. Apply enough gentle pressure on the individual vial 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% solution in the affected eye(s) administered twice a day. Since in some patients the pressure-lowering response to preservative-free timolol maleate ophthalmic solution in the unit dose vial may require a few weeks to stabilize, evaluation should include a determination of intraocular pressure after approximately 4 weeks of treatment with preservative-free timolol maleate ophthalmic solution in the unit dose vial. 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% 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 PRECAUTIONS , Drug Interactions, Beta-adrenergic blocking agents .)
Contraindications
4 CONTRAINDICATIONS
- Bronchial asthma, a history of bronchial asthma, severe chronic obstructive pulmonary disease ( 4.1 , 5.1 , 5.3 )
- Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, cardiogenic shock ( 4.2 , 5.2 )
- Hypersensitivity to any component of this product ( 4.3 )
4.1 Asthma, COPD Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span>.
4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .
4.3 Hypersensitivity Reactions Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.
4.1 Asthma, COPD Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with bronchial asthma; a history of bronchial asthma; severe chronic obstructive pulmonary disease <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.1 , 5.3 )]</span>.
4.2 Sinus Bradycardia, AV Block, Cardiac Failure, Cardiogenic Shock Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients with sinus bradycardia; second or third degree atrioventricular block; overt cardiac failure; cardiogenic shock <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> .
4.3 Hypersensitivity Reactions Timolol Maleate Ophthalmic Solution 0.5% is contraindicated in patients who have exhibited a hypersensitivity reaction to any component of this product in the past.
Known Adverse Reactions
REACTIONS The most frequently reported adverse reactions have been burning and stinging upon instillation in 38% of patients treated with Timolol Maleate Ophthalmic Solution. Additional reactions reported with Timolol Maleate Ophthalmic Solution at a frequency of 4% to 10% include: blurred vision, cataract, conjunctival injection, headache, hypertension, infection, itching and decreased visual acuity. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions have been burning and stinging upon instillation in 38% of patients treated with Timolol Maleate Ophthalmic Solution. Additional reactions reported with Timolol Maleate Ophthalmic Solution 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 reactions have been reported less frequently with ocular administration of this or other timolol maleate formulations. Timolol (Ocular Administration) Body as a Whole: Asthenia/fatigue and chest pain; Cardiovascular: Bradycardia, 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; 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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span>; 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span>; Urogenital: Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie’s disease.
6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Timolol Maleate Ophthalmic Solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Oral Timolol/Oral
Beta-Blockers 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.
6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most frequently reported adverse reactions have been burning and stinging upon instillation in 38% of patients treated with Timolol Maleate Ophthalmic Solution. Additional reactions reported with Timolol Maleate Ophthalmic Solution 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 reactions have been reported less frequently with ocular administration of this or other timolol maleate formulations. Timolol (Ocular Administration) Body as a Whole: Asthenia/fatigue and chest pain; Cardiovascular: Bradycardia, 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; 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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.6 )]</span>; 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span>; Urogenital: Retroperitoneal fibrosis, decreased libido, impotence, and Peyronie’s disease.
6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of Timolol Maleate Ophthalmic Solution. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Oral Timolol/Oral
Beta-Blockers 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.
Warnings
AND PRECAUTIONS Potentiation of Respiratory Reactions Including Asthma ( 5.1 )
Cardiac
Failure ( 5.2 )
Obstructive Pulmonary
Disease ( 5.3 )
Increased
Reactivity to Allergens ( 5.4 ) Potentiation of Muscle Weakness ( 5.5 ) Masking of Hypoglycemic Symptoms in Patients with Diabetes Mellitus ( 5.6 ) Masking of Thyrotoxicosis ( 5.7 )
5.1 Potentiation of Respiratory Reactions Including Asthma Timolol Maleate Ophthalmic Solution contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical 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 <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.
5.2 Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition of 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, Timolol Maleate Ophthalmic Solution should be discontinued <span class="opacity-50 text-xs">[see Contraindications ( 4.2 )]</span>.
5.3 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 Timolol Maleate Ophthalmic Solution is contraindicated] should, in general, not receive beta-blocking agents, including Timolol Maleate Ophthalmic Solution <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.
5.4 Increased Reactivity to Allergens 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.
5.5 Potentiation of 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.
5.6 Masking of Hypoglycemic Symptoms in Patients with 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.
5.7 Masking of 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.
5.8 Contamination of Topical Ophthalmic Products After Use 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span>.
5.9 Impairment of Beta-adrenergically Mediated Reflexes During 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.
5.10 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.
Timolol Maleate Ophthalmic
Solution should not be used alone in the treatment of angle-closure glaucoma.
5.11 Cerebrovascular Insufficiency 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 Timolol Maleate Ophthalmic Solution, alternative therapy should be considered.
5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
5.13 Contact Lens Use Timolol Maleate Ophthalmic Solution contains benzalkonium chloride, an anti-microbial preservative 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 Timolol Maleate Ophthalmic Solution administration.
5.1 Potentiation of Respiratory Reactions Including Asthma Timolol Maleate Ophthalmic Solution contains timolol maleate; and although administered topically, it can be absorbed systemically. Therefore, the same adverse reactions found with systemic administration of beta-adrenergic blocking agents may occur with topical 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 <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.
5.2 Cardiac Failure Sympathetic stimulation may be essential for support of the circulation in individuals with diminished myocardial contractility, and its inhibition of 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, Timolol Maleate Ophthalmic Solution should be discontinued <span class="opacity-50 text-xs">[see Contraindications ( 4.2 )]</span>.
5.3 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 Timolol Maleate Ophthalmic Solution is contraindicated] should, in general, not receive beta-blocking agents, including Timolol Maleate Ophthalmic Solution <span class="opacity-50 text-xs">[see Contraindications ( 4.1 )]</span>.
5.4 Increased Reactivity to Allergens 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.
5.5 Potentiation of 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.
5.6 Masking of Hypoglycemic Symptoms in Patients with 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.
5.7 Masking of 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.
5.8 Contamination of Topical Ophthalmic Products After Use 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 <span class="opacity-50 text-xs">[see Patient Counseling Information ( 17 )]</span>.
5.9 Impairment of Beta-adrenergically Mediated Reflexes During 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.
5.10 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.
Timolol Maleate Ophthalmic
Solution should not be used alone in the treatment of angle-closure glaucoma.
5.11 Cerebrovascular Insufficiency 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 Timolol Maleate Ophthalmic Solution, alternative therapy should be considered.
5.12 Choroidal Detachment Choroidal detachment after filtration procedures has been reported with the administration of aqueous suppressant therapy (e.g., timolol).
Precautions
PRECAUTIONS 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 Timolol Maleate Ophthalmic Gel Forming Solution, 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 ]. 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.
Timolol Maleate Ophthalmic Gel Forming
Solution 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. 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 [see PRECAUTIONS , General ]. 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 Timolol Maleate Ophthalmic Gel Forming Solution. 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 ]. 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.
Drug Interactions
Beta-Adrenergic Blocking Agents Patients who are receiving a beta-adrenergic blocking agent orally and Timolol Maleate Ophthalmic Gel Forming Solution 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 Timolol Maleate Ophthalmic Gel Forming Solution, 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 [See PRECAUTIONS , General , Anaphylaxis ] 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 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 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.
Pregnancy Teratogenic Effects
Teratogenicity studies with timolol in mice, rats, and rabbits at oral doses up to 50 mg/kg/day (7,000 times the systemic exposure following the maximum recommended human ophthalmic dose) demonstrated no evidence of fetal malformations. Although delayed fetal ossification was observed at this dose in rats, there were no adverse effects on postnatal development of offspring. Doses of 1,000 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.
Timolol Maleate Ophthalmic Gel Forming
Solution should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
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 Timolol Maleate Ophthalmic Gel Forming Solution 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.
Pediatric Use
Safety and effectiveness of timolol maleate ophthalmic solution have been established when administered in pediatric patients aged 2 years and older. Use of timolol maleate ophthalmic solution in these children is supported by evidence from adequate and well-controlled studies in children and adults. Safety and efficacy in pediatric patients below the age of 2 years have not been established.
Geriatric
Use No overall differences in safety or effectiveness have been observed between elderly and younger patients.
Drug Interactions
INTERACTIONS
- Concomitant use with systemic beta-blockers may potentiate systemic beta-blockade. ( 7.1 )
- Oral or intravenous calcium antagonists may cause atrioventricular conduction disturbances, left ventricular failure, and hypotension. ( 7.2 )
- Catecholamine-depleting drugs may have additive effects and produce hypotension and/or marked bradycardia. ( 7.3 )
- Digitalis and calcium antagonists may have additive effects in prolonging atrioventricular conduction time. ( 7.4 )
- Potentiated systemic beta-blockade (e.g., decreased heart rate) has been reported during combined treatment with quinidine and timolol. ( 7.5 )