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Timolol (Ophthalmic)


General


Pronunciation

(TIM oh lol)


Brand Names: U.S.

  • Betimol
  • Istalol
  • Timoptic
  • Timoptic Ocudose
  • Timoptic-XE

Indications


Use: Labeled Indications

Elevated intraocular pressure: Treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma


Contraindications


Bronchial asthma or history of bronchial asthma; severe chronic obstructive pulmonary disease (COPD); sinus bradycardia; second- or third-degree atrioventricular block; overt cardiac failure; cardiogenic shock; or hypersensitivity to timolol or any component of the formulation.

Documentation of allergenic cross-reactivity for Ophthalmic Beta-Adrenergic Blocking Agents is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.


Dosing and Administration


Dosing: Adult

Elevated intraocular pressure: Ophthalmic:

Gel-forming solution (Timolol GFS, Timoptic-XE): Instill 1 drop (either 0.25% or 0.5% solution) once daily

Solution: Initial: Instill 1 drop (0.25% solution) into affected eye(s) twice daily; if response is not adequate, increase to 1 drop (0.5% solution) twice daily. May decrease dose to 1 drop once daily if intraocular pressure is well controlled (maximum dose: 1 drop twice daily of 0.5% solution)

Istalol: Instill 1 drop (0.5% solution) once daily in the morning


Dosing: Geriatric

Refer to adult dosing.


Dosing: Pediatric

Elevated intraocular pressure: Infants, Children, and Adolescents: Ophthalmic: Use lowest effective dose; the gel formulation may be preferable due to decreased systemic absorption (Coppens, 2009).

Gel-forming solution (Timolol GFS, Timoptic-XE): Instill 1 drop (either 0.25% or 0.5%) once daily into affected eye(s) (Coppens 2009; Moore 2007)

Solution: Limited data available: Initial: 0.25% solution, instill 1 drop twice daily into affected eye(s); increase to 0.5% solution if response not adequate; decrease to 1 drop once daily into affected eye(s) if controlled; maximum dose: 1 drop (0.5% solution)/dose (Hoskins 1985; Moore 2007).


Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer 's labeling.


Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer 's labeling.


Administration

For topical ophthalmic use only. Wash hands before use; invert closed bottle and shake gel-forming solutions once before use. Hold bottle between thumb and index finger; use index finger of other hand to pull down the lower eyelid to form a pocket for the eye drop and tilt head back; place the dispenser tip close to the eye and gently squeeze the bottle to administer 1 drop. If more than one topical ophthalmic drug is being used, administer drugs at least 5 to 10 minutes apart. Some products contain benzalkonium chloride; wait at least 10 to 15 minutes after instilling solution before inserting soft contact lenses. Minimize contamination by not touching the eyelids or surrounding areas with the dropper tip; keep bottle tightly closed when not in use. Do not enlarge hole of dispenser tip.


Storage

Store at 15 ‚ °C to 30 ‚ °C (59 ‚ °F to 86 ‚ °F); do not freeze. Protect from light.

Timoptic in OcuDose: Store in the protective foil wrap and use within 1 month after opening foil package.


Dosage Forms/Strengths


Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Gel Forming Solution, Ophthalmic, as maleate [strength expressed as base]:

Timoptic-XE: 0.25% (5 mL); 0.5% (5 mL)

Generic: 0.25% (5 mL); 0.5% (5 mL)

Solution, Ophthalmic, as hemihydrate [strength expressed as base]:

Betimol: 0.25% (5 mL); 0.5% (5 mL, 10 mL, 15 mL) [contains benzalkonium chloride]

Solution, Ophthalmic, as maleate [strength expressed as base]:

Istalol: 0.5% (2.5 mL, 5 mL) [contains benzalkonium chloride]

Timoptic: 0.25% (5 mL); 0.5% (5 mL, 10 mL) [contains benzalkonium chloride]

Generic: 0.25% (5 mL, 10 mL, 15 mL); 0.5% (5 mL, 10 mL, 15 mL)

Solution, Ophthalmic, as maleate [strength expressed as base, preservative free]:

Timoptic Ocudose: 0.25% (60 ea); 0.5% (60 ea)


Drug Interactions

Abiraterone Acetate: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of abiraterone with CYP2D6 substrates that have a narrow therapeutic index whenever possible. When concurrent use is not avoidable, monitor patients closely for signs/symptoms of toxicity. Consider therapy modification

Acetylcholinesterase Inhibitors: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Ajmaline: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Alpha-/Beta-Agonists (Direct-Acting): Beta-Blockers may enhance the vasopressor effect of Alpha-/Beta-Agonists (Direct-Acting). Epinephrine used as a local anesthetic for dental procedures will not likely cause clinically relevant problems. Some beta-adrenoceptor mediated effects of Alpha-/Beta-Agonists (Direct-Acting), including anti-anaphylactic effects of epinephrine, may be diminished by Beta-Blockers. Management: Cardioselective beta-blockers and lower doses of epinephrine may confer a more limited risk. Patients who may require acute subcutaneous epinephrine (e.g., bee sting kits) should probably avoid beta blockers. Exceptions: Dipivefrin. Consider therapy modification

Alpha1-Blockers: Beta-Blockers may enhance the orthostatic hypotensive effect of Alpha1-Blockers. The risk associated with ophthalmic products is probably less than systemic products. Monitor therapy

Alpha2-Agonists: May enhance the AV-blocking effect of Beta-Blockers. Sinus node dysfunction may also be enhanced. Beta-Blockers may enhance the rebound hypertensive effect of Alpha2-Agonists. This effect can occur when the Alpha2-Agonist is abruptly withdrawn. Management: Closely monitor heart rate during treatment with a beta blocker and clonidine. Withdraw beta blockers several days before clonidine withdrawal when possible, and monitor blood pressure closely. Recommendations for other alpha2-agonists are unavailable. Exceptions: Apraclonidine. Consider therapy modification

Aminoquinolines (Antimalarial): May decrease the metabolism of Beta-Blockers. Monitor therapy

Amiodarone: May enhance the bradycardic effect of Beta-Blockers. Possibly to the point of cardiac arrest. Amiodarone may increase the serum concentration of Beta-Blockers. Monitor therapy

Anilidopiperidine Opioids: May enhance the bradycardic effect of Beta-Blockers. Anilidopiperidine Opioids may enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Antipsychotic Agents (Phenothiazines): May enhance the hypotensive effect of Beta-Blockers. Beta-Blockers may decrease the metabolism of Antipsychotic Agents (Phenothiazines). Antipsychotic Agents (Phenothiazines) may decrease the metabolism of Beta-Blockers. Monitor therapy

Asunaprevir: May increase the serum concentration of CYP2D6 Substrates. Consider therapy modification

Barbiturates: May decrease the serum concentration of Beta-Blockers. Monitor therapy

Beta2-Agonists: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Beta2-Agonists. Avoid combination

Bradycardia-Causing Agents: May enhance the bradycardic effect of other Bradycardia-Causing Agents. Monitor therapy

Bretylium: May enhance the bradycardic effect of Bradycardia-Causing Agents. Bretylium may also enhance atrioventricular (AV) blockade in patients receiving AV blocking agents. Monitor therapy

Bupivacaine: Beta-Blockers may increase the serum concentration of Bupivacaine. Monitor therapy

Calcium Channel Blockers (Nondihydropyridine): May enhance the hypotensive effect of Beta-Blockers. Bradycardia and signs of heart failure have also been reported. Calcium Channel Blockers (Nondihydropyridine) may increase the serum concentration of Beta-Blockers. Exceptions: Bepridil. Monitor therapy

Cardiac Glycosides: Beta-Blockers may enhance the bradycardic effect of Cardiac Glycosides. Monitor therapy

Ceritinib: Bradycardia-Causing Agents may enhance the bradycardic effect of Ceritinib. Management: If this combination cannot be avoided, monitor patients for evidence of symptomatic bradycardia, and closely monitor blood pressure and heart rate during therapy. Avoid combination

Cholinergic Agonists: Beta-Blockers may enhance the adverse/toxic effect of Cholinergic Agonists. Of particular concern are the potential for cardiac conduction abnormalities and bronchoconstriction. Management: Administer these agents in combination with caution, and monitor for conduction disturbances. Avoid methacholine with any beta blocker due to the potential for additive bronchoconstriction. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Moderate): May decrease the metabolism of CYP2D6 Substrates. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

Darunavir: May increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Dipyridamole: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Disopyramide: May enhance the bradycardic effect of Beta-Blockers. Beta-Blockers may enhance the negative inotropic effect of Disopyramide. Monitor therapy

Dronedarone: May enhance the bradycardic effect of Beta-Blockers. Dronedarone may increase the serum concentration of Beta-Blockers. This likely applies only to those agents that are metabolized by CYP2D6. Management: Use lower initial beta-blocker doses; adequate tolerance of the combination, based on ECG findings, should be confirmed prior to any increase in beta-blocker dose. Consider therapy modification

Ergot Derivatives: Beta-Blockers may enhance the vasoconstricting effect of Ergot Derivatives. Exceptions: Nicergoline. Consider therapy modification

Fingolimod: Beta-Blockers may enhance the bradycardic effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and beta-blockers if possible. If coadministration is necessary, patients should have overnight continuous ECG monitoring conducted after the first dose of fingolimod. Monitor patients for bradycardia. Consider therapy modification

Floctafenine: May enhance the adverse/toxic effect of Beta-Blockers. Avoid combination

Grass Pollen Allergen Extract (5 Grass Extract): Beta-Blockers may enhance the adverse/toxic effect of Grass Pollen Allergen Extract (5 Grass Extract). More specifically, Beta-Blockers may inhibit the ability to effectively treat severe allergic reactions to Grass Pollen Allergen Extract (5 Grass Extract) with epinephrine. Some other effects of epinephrine may be unaffected or even enhanced (e.g., vasoconstriction) during treatment with Beta-Blockers. Consider therapy modification

Insulin: Beta-Blockers may enhance the hypoglycemic effect of Insulin. Monitor therapy

Ivabradine: Bradycardia-Causing Agents may enhance the bradycardic effect of Ivabradine. Monitor therapy

Lacosamide: Bradycardia-Causing Agents may enhance the AV-blocking effect of Lacosamide. Monitor therapy

Lidocaine (Systemic): Beta-Blockers may increase the serum concentration of Lidocaine (Systemic). Monitor therapy

Lidocaine (Topical): Beta-Blockers may increase the serum concentration of Lidocaine (Topical). Monitor therapy

Mepivacaine: Beta-Blockers may increase the serum concentration of Mepivacaine. Monitor therapy

Methacholine: Beta-Blockers may enhance the adverse/toxic effect of Methacholine. Avoid combination

Midodrine: Beta-Blockers may enhance the bradycardic effect of Midodrine. Monitor therapy

NIFEdipine: May enhance the hypotensive effect of Beta-Blockers. NIFEdipine may enhance the negative inotropic effect of Beta-Blockers. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Beta-Blockers. Monitor therapy

Panobinostat: May increase the serum concentration of CYP2D6 Substrates. Management: Avoid concurrent use of sensitive CYP2D6 substrates when possible, particularly those substrates with a narrow therapeutic index. Consider therapy modification

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates. Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Perhexiline: CYP2D6 Substrates may increase the serum concentration of Perhexiline. Perhexiline may increase the serum concentration of CYP2D6 Substrates. Monitor therapy

Propafenone: May increase the serum concentration of Beta-Blockers. Propafenone possesses some independent beta blocking activity. Monitor therapy

Regorafenib: May enhance the bradycardic effect of Beta-Blockers. Monitor therapy

Reserpine: May enhance the hypotensive effect of Beta-Blockers. Monitor therapy

Rifamycin Derivatives: May decrease the serum concentration of Beta-Blockers. Exceptions: Rifabutin. Monitor therapy

Rivastigmine: May enhance the bradycardic effect of Beta-Blockers. Avoid combination

Ruxolitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Management: Ruxolitinib Canadian product labeling recommends avoiding use with bradycardia-causing agents to the extent possible. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May increase the serum concentration of Beta-Blockers. Exceptions: Citalopram; Escitalopram; FluvoxaMINE. Monitor therapy

Sulfonylureas: Beta-Blockers may enhance the hypoglycemic effect of Sulfonylureas. Cardioselective beta-blockers (eg, acebutolol, atenolol, metoprolol, and penbutolol) may be safer than nonselective beta-blockers. All beta-blockers appear to mask tachycardia as an initial symptom of hypoglycemia. Ophthalmic beta-blockers are probably associated with lower risk than systemic agents. Monitor therapy

Theophylline Derivatives: Beta-Blockers (Nonselective) may diminish the bronchodilatory effect of Theophylline Derivatives. Consider therapy modification

Tofacitinib: May enhance the bradycardic effect of Bradycardia-Causing Agents. Monitor therapy


Monitoring Parameters

Intraocular pressure (after ~4 weeks of therapy)


Adverse Reactions


>10%: Ocular: Burning, stinging

Frequency not defined:

Cardiovascular: Angina pectoris, arrhythmia, bradycardia, cardiac arrest, cardiac failure, cerebral ischemia, cerebral vascular accident, edema, heart block, hypertension, hypotension, palpitation, Raynauds phenomenon

Central nervous system: Anxiety, confusion, depression, disorientation, dizziness, hallucinations, headache, insomnia, memory loss, nervousness, nightmares, somnolence

Dermatologic: Alopecia, angioedema, pseudopemphigoid, psoriasiform rash, psoriasis exacerbation, rash, urticaria

Endocrine & metabolic: Hypoglycemia masked, libido decreased

Gastrointestinal: Anorexia, diarrhea, dyspepsia, nausea, xerostomia

Genitourinary: Impotence, retoperitoneal fibrosis

Hematologic: Claudication

Neuromuscular & skeletal: Myasthenia gravis exacerbation, paresthesia

Ocular: Blepharitis, blurred vision, cataract, choroidal detachment (following filtration surgery), conjunctival injection, conjunctivitis, corneal sensitivity decreased, cystoid macular edema, diplopia, dry eyes, foreign body sensation, hyperemia, itching, keratitis, ocular discharge, ocular pain, ptosis, tearing, visual acuity decreased refractive changes, visual disturbances

Otic: Tinnitus

Respiratory: Bronchospasm, cough, dyspnea, nasal congestion, pulmonary edema, respiratory failure

Miscellaneous: Allergic reactions, cold hands/feet, Peyronie's disease, systemic lupus erythematosus


Warnings/Precautions


Concerns related to adverse events:

- Anaphylactic reactions: Use caution with history of severe anaphylaxis to allergens; patients taking beta-blockers may become more sensitive to repeated challenges. Treatment of anaphylaxis (eg, epinephrine) in patients taking beta-blockers may be ineffective or promote undesirable effects.

- Choroidal detachment: Beta-blockade and/or other suppressive therapy have been associated with choroidal detachment following filtration procedures.

Disease-related concerns:

- Bronchospastic disease: In general, patients with bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring. Severe respiratory reactions, including fatalities, have been reported with ophthalmic use. Use is contraindicated in bronchial asthma or history of bronchial asthma and severe COPD.

- Conduction abnormality: Consider preexisting conditions, such as sick sinus syndrome, before initiating.

- Diabetes: Use with caution in patients with diabetes mellitus; may potentiate hypoglycemia and/or mask signs and symptoms.

- Heart failure: Use with caution in patients with compensated heart failure and monitor for a worsening of the condition; may lead to heart failure in patients without a history of heart failure. Use is contraindicated in overt heart failure.

- Myasthenia gravis: Use with caution in patients with myasthenia gravis or myasthenic symptoms; may worsen disease.

- Peripheral vascular disease (PVD) and Raynaud disease: Can precipitate or aggravate symptoms of arterial insufficiency in patients with PVD and Raynaud disease. Use with caution and monitor for progression of arterial obstruction.

- Thyroid disease: May mask signs of hyperthyroidism (eg, tachycardia). If thyrotoxicosis is suspected, carefully manage and monitor; abrupt withdrawal may exacerbate symptoms of hyperthyroidism or precipitate thyroid storm.

Concurrent drug therapy issues:

- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information

Special populations:

- Contact lens wearers: Some products contain benzalkonium chloride, which may be absorbed by soft contact lenses; remove lens prior to administration and wait 15 minutes before reinserting.

Other warnings/precautions:

- Absorption: Systemic absorption of timolol and adverse effects may occur with ophthalmic use, including respiratory and cardiovascular effects (eg, bradycardia and/or hypotension). Beta-blocker therapy should not be withdrawn abruptly in order to avoid acute tachycardia, hypertension, and/or ischemia. Patients undergoing major surgery should be gradually tapered off therapy prior to procedure.

- Appropriate use: Should not be used alone in angle-closure glaucoma (has no effect on pupillary constriction). Concomitant use of 2 topical beta-blockers is not recommended. Multidose vials have been associated with development of bacterial keratitis; avoid contamination.


Pregnancy Risk Factor

C


Pregnancy Considerations

Adverse events were observed in some animal reproduction studies. Decreased fetal heart rate has been observed following maternal use of ophthalmic timolol during pregnancy (Wagenvoort 1998). Timolol is absorbed systemically following ophthalmic use; additional adverse effects observed with systemic administration may occur. If ophthalmic agents are needed to treat glaucoma in pregnancy, the minimum effective dose should be used in combination with punctal occlusion to decrease exposure to the fetus (Johnson 2001; Salim 2014; Wagenvoort 1998).


Actions


Pharmacology

Blocks both beta1- and beta2-adrenergic receptors and reduces intraocular pressure by reducing aqueous humor production or possibly increases the outflow of aqueous humor


Absorption

Solution: Timolol is measurable in the serum following ophthalmic use


Onset of Action

Solution: Intraocular pressure reduction: 30 minutes; Peak effect: 1 to 2 hours


Duration of Action

Solution: 24 hours


Half-Life Elimination

4 hours


Patient and Family Education


Patient Education

- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

- Patient may experience burning, headache, signs of common cold, or stinging. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), vision changes, eye pain, severe eye irritation, shortness of breath, excessive weight gain, swelling of arms or legs, severe dizziness, passing out, bradycardia, or muscle weakness (HCAHPS).

- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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