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Latanoprost and Timolol

Pronunciation

(la TA noe prost & TIM oh lol)

Index Terms

  • Timolol Maleate and Latanoprost

Pharmacologic Category

  • Beta-Blocker, Nonselective
  • Ophthalmic Agent, Antiglaucoma
  • Prostaglandin, Ophthalmic

Pharmacology

Latanoprost: A prostaglandin F2-alpha analog believed to reduce intraocular pressure by increasing the outflow of the aqueous humor

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

Use: Labeled Indications

Note: Not approved in the US

Elevated intraocular pressure: Reduction of intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-blockers, prostaglandin analogues, or other IOP-reducing agents and in whom combination therapy is appropriate

Contraindications

Hypersensitivity to latanoprost, timolol, benzalkonium chloride, or any component of the formulation; reactive airway disease including severe chronic obstructive pulmonary disease (COPD) and presence or history of bronchial asthma; sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled with pacemaker, overt cardiac failure, cardiogenic shock

Dosing: Adult

Elevated intraocular pressure: Ophthalmic: Instill 1 drop into affected eye(s) once daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use caution.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied); use caution.

Administration

Ophthalmic: Wash hands prior to use. Remove contact lenses prior to administration; wait 15 minutes before reinserting if using products containing benzalkonium chloride. Separate administration of other ophthalmic agents by 5 minutes. Nasolacrimal occlusion or closing the eye for 2 minutes after administration may limit systemic absorption.

Storage

Prior to opening, store at 2°C to 8°C (36°F to 46°F). After opening may store up to 25°C (77°F) for 10 weeks. Protect from light.

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

Bimatoprost: The concomitant use of Latanoprost and Bimatoprost may result in increased intraocular pressure. Consider therapy modification

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

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

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

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates. 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

Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Prostaglandins (Ophthalmic). Nonsteroidal Anti-Inflammatory Agents may also enhance the therapeutic effects of Prostaglandins (Ophthalmic). 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

QuiNINE: May increase the serum concentration of CYP2D6 Substrates. 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

Adverse Reactions

Percentages as reported with combination product. Also see individual agents.

>10%: Ophthalmic: Abnormal eyelash growth (including darkening, lengthening, thickening; 37%), iris hyperpigmentation (2% to 20%; color change due to increase melanin content and is most common in mixed color irises), eye irritation (12%)

1% to 10%:

Cardiovascular: Hypertension (4%), chest pain (1%)

Central nervous system: Depression (2%), headache (2%)

Dermatologic: Dermatological disease (2%), skin rash (1%)

Endocrine & metabolic: Hypercholesterolemia (2%), diabetes mellitus (1%)

Infection: Infection (1%)

Neuromuscular & skeletal: Arthritis (2%), back pain (1%)

Ophthalmic: Ocular hyperemia (7%), visual disturbance (7%), visual field defect (5%), blepharitis (3%), cataract (3%), conjunctivitis (3%), corneal disorder (3%), eye pain (2%), photophobia (2%), error of refraction (2%), conjunctival disease (1%), keratitis (1%)

Respiratory: Upper respiratory tract infection (6%), flu-like symptoms (3%), sinusitis (2%)

<1% (Limited to important or life-threatening): Bronchitis, cardiac failure, corneal ulcer, cystitis, cystoid macular edema, dizziness, dyspepsia, dyspnea, epiphora, exacerbation of hypertension, eyelid edema, glycosuria, hyperglycemia, increased intraocular pressure, insomnia, optic atrophy, pneumonia, retinopathy, seborrhea, skin discoloration, urinary tract infection, uveitis

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylactic reactions: Use caution with history of atopy or 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.

• Bacterial keratitis: Inadvertent contamination of multiple-dose ophthalmic solutions has caused bacterial keratitis.

• Ocular effects: Use of agents that reduce/suppress aqueous humor production has been associated with choroidal detachment after filtration procedures. Discontinue use in patients with chronic or recurrent choroidal detachment. Macular edema (including cystoid macular edema), mainly in aphakic or pseudophakic patients with a torn posterior lens capsule, has been associated with use of prostaglandin analogues such as latanoprost. May permanently change/increase brown pigmentation of the iris, the eyelid skin, and eyelashes. Patients should be examined regularly and, depending on the clinical situation, treatment may be stopped if increased iris pigmentation ensues. In addition, may increase the length, darken and thicken eyelashes (may vary between eyes); changes occur slowly and may not be noticeable for months or years. Long-term consequences and potential injury to eye are not known. Ophthalmic beta-blockers may cause eye dryness; use caution in corneal diseases.

Disease-related concerns:

• Cardiovascular disease: Consider pre-existing conduction abnormalities prior to initiation; use is contraindicated in several conditions (refer to contraindications). Use with caution in first-degree heart block. Use with caution in heart failure (HF); fatalities have been reported. Prior to initiating therapy HF should be controlled. Monitor for signs/symptoms of HF and discontinue use immediately if suspected. Use with caution in patients with orthostatic hypotension; signs and symptoms of hypotension may be enhanced.

• Closed-angle glaucoma: Should not be used alone in the treatment of acute closed angle glaucoma (immediate objective is to reopen the angle by constricting the pupil). Latanoprost and timolol maleate have little or no effect on the pupil.

• Diabetes: Use with caution in patients with diabetes mellitus (especially labile diabetes); may potentiate hypoglycemia and/or mask signs and symptoms.

• Hepatic impairment: Use with caution in hepatic impairment (has not been studied).

• Herpetic keratitis: Use with caution in patients with a history of herpes simplex keratitis; reactivation may occur. Avoid use in patients with active herpes simplex keratitis or patients with a history of recurrent herpetic keratitis specifically associated with prostaglandin analogs.

• Iritis/uveitis: Use caution in patients with active intraocular inflammation.

• Myasthenia gravis: Use with caution in patients with myasthenia gravis; may worsen disease or other myasthenic symptoms (diplopia, ptosis, generalized weakness).

• 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.

• Pulmonary disease: Use with caution in patients with mild or moderate COPD and closely monitor; beta blockers should generally be avoided in patients with bronchospastic disease.

• Renal impairment: Use with caution in renal impairment (has not been studied).

• 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.

• Thimerosal: Precipitation may occur if mixed with benzalkonium chloride-containing products; allow at least 5 minutes between the application of latanoprost/timolol and ophthalmic preparations containing thimerosal.

Special populations:

• Contact lens wearers: Product contains 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 bradycardia and/or hypotension. Beta-blocker therapy should not be withdrawn abruptly in order to avoid acute tachycardia, hypertension, and/or ischemia. In patients undergoing major surgery, anesthesia provider should be informed that patient is receiving timolol; gradually taper off therapy prior to procedure if possible.

• Appropriate use: Limited or no experience in the treatment of chronic angle-closure, congenital, inflammatory, neovascular, or pigmentary glaucoma or in pseudophakic patients with open angle glaucoma.

• Initial therapy: Combination product should not be used for initial therapy.

Monitoring Parameters

IOP, iris color changes, eyelash changes; systemic effects of beta blockade

Pregnancy Considerations

Reproductive studies have not been conducted with this combination. See individual agents.

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