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Dorzolamide and Timolol

Pronunciation

(dor ZOLE a mide & TYE moe lole)

Index Terms

  • Dorzolamide HCl/Timolol Maleate
  • Timolol and Dorzolamide

Dosage Forms

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

Solution, ophthalmic [drops]:

Cosopt: Dorzolamide 2% [20 mg/mL] and timolol 0.5% [5 mg/mL] (10 mL) [contains benzalkonium chloride]

Generic: Dorzolamide 2% [20 mg/mL] and timolol 0.5% [5 mg/mL] (10 mL)

Solution, ophthalmic [drops, preservative free]:

Cosopt PF: Dorzolamide 2% [20 mg/mL] and timolol 0.5% [5 mg/mL] (0.2 mL)

Brand Names: U.S.

  • Cosopt
  • Cosopt PF

Pharmacologic Category

  • Beta-Adrenergic Blocker, Nonselective
  • Carbonic Anhydrase Inhibitor (Ophthalmic)
  • Ophthalmic Agent, Antiglaucoma

Pharmacology

Dorzolamide: Inhibits carbonic anhydrase in the ciliary processes of the eye resulting decreased bicarbonate ion formation which decreases sodium and fluid transport, thus decreasing aqueous humor secretion and reduces intraocular pressure.

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

Elevated intraocular pressure: Reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to beta-blockers

Contraindications

Hypersensitivity to dorzolamide, timolol, or any component of the formulation; bronchial asthma or a history of bronchial asthma; severe chronic obstructive pulmonary disease; sinus bradycardia; second- or third-degree atrioventricular block; overt cardiac failure; cardiogenic shock.

Dosing: Adult

Elevated intraocular pressure: Ophthalmic: Instill 1 drop in affected eye(s) twice daily

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Elevated intraocular pressure: Children ≥2 years and Adolescents: Ophthalmic: Refer to adult dosing.

Dosing: Renal Impairment

CrCl ≥30 mL/minute: No dosage adjustment necessary.

CrCl <30 mL/minute: Use is not recommended (has not been studied).

Dosing: Hepatic Impairment

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

Administration

Ophthalmic:

Cosopt: If using additional topical ophthalmic preparations, separate administration by at least 5 minutes. Remove contact lens prior to administration and wait 15 minutes before reinserting. Instruct patients to avoid allowing the tip of the dispensing container to contact the eye or surrounding structures. Ocular solutions can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may occur from using contaminated solutions.

Cosopt PF: Discard single-use container after initial use. If using additional topical ophthalmic preparations, separate administration by at least 5 minutes.

Storage

Store at 15°C to 30°C (59°F to 86°F). Protect from light.

Cosopt PF: Unused single-use containers may be stored in the opened foil pouch for up to 15 days. Do not freeze.

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

Alpha-/Beta-Agonists (Indirect-Acting): Carbonic Anhydrase Inhibitors may increase the serum concentration of Alpha-/Beta-Agonists (Indirect-Acting). Monitor therapy

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

Carbonic Anhydrase Inhibitors: May enhance the adverse/toxic effect of other Carbonic Anhydrase Inhibitors. The development of acid-base disorders with concurrent use of ophthalmic and oral carbonic anhydrase inhibitors has been reported. Management: Avoid concurrent use of different carbonic anhydrase inhibitors if possible. Monitor patients closely for the occurrence of kidney stones and with regards to severity of metabolic acidosis. Avoid combination

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

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

Frequency not always defined. Percentages as reported with combination product. Also see individual agents.

>5%:

Gastrointestinal: Dysgeusia (≤30%)

Ophthalmic: Burning sensation of eyes (≤30%), stinging of eyes (≤30%), blurred vision (5% to 15%), conjunctival hyperemia (5% to 15%), eye pruritus (5% to 15%), superficial punctate keratitis (5% to 15%)

1% to 5%:

Cardiovascular: Hypertension

Central nervous system: Dizziness, headache

Dermatologic: Erythema of eyelid

Gastrointestinal: Abdominal pain, dyspepsia, nausea

Genitourinary: Urinary tract infection

Infection: Influenza

Neuromuscular & skeletal: Back pain

Ophthalmic: Blepharitis, cataract (including post-subcapsular), cloudy vision, conjunctival discharge, conjunctival edema, conjunctivitis, corneal erosion, corneal staining, dry eye syndrome, eye discharge (including eyelid), eye disease (debris in eye), eye pain (includes eyelid), eyelid edema, follicular conjunctivitis, foreign body sensation of eye, lacrimation, lens nucleus discoloration, ocular exudate (eyelid), optic disk cupping (glaucomatous), scaling of eyelid, visual field defect, vitreous detachment

Respiratory: Bronchitis, cough, pharyngitis, sinusitis, upper respiratory tract infection

<1% (Limited to important or life-threatening): Bradycardia, cardiac failure, cerebrovascular accident, chest pain, choroidal detachment (following filtration procedures), depression, diarrhea, dyspnea, heart block, hypotension, iridocyclitis, myocardial infarction, nasal congestion, paresthesia, photophobia, respiratory failure, skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, urolithiasis, vomiting, xerostomia

Warnings/Precautions

Concerns related to adverse effects:

• 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.

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

• Ocular effects: Local ocular adverse effects (conjunctivitis and lid reactions) were reported with chronic administration; many resolved upon discontinuation of drug therapy. Choroidal detachment has been reported after filtration procedures. Patients with low endothelial cell counts may have increased risk for corneal edema; use caution.

• Sulfonamide (“sulfa”) allergy: Dorzolamide is a sulfonamide; although administered ocularly, systemic absorption may occur and could result in hypersensitivity. Discontinue use if signs of hypersensitivity or a serious reaction occur.

• Systemic effects: Systemic absorption and adverse effects (similar to sulfonamides) including blood dyscrasias, Stevens-Johnson syndrome, toxic epidermal necrolysis, and fulminant hepatic necrosis may occur with ophthalmic use.

Disease-related concerns:

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

• Heart failure (HF): Use with caution in patients with compensated heart failure and monitor for a worsening of the condition; control heart failure prior to initiation of therapy.

• Hepatic impairment: Use with caution in patients with hepatic impairment; not evaluated.

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

• Narrow-angle glaucoma: Use is not recommended in narrow-angle glaucoma (has not been studied).

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

• Psychiatric disease: Use with caution in patients with a history of psychiatric illness; may cause or exacerbate CNS depression.

• Renal impairment: Use with caution in patients with renal impairment; not recommended with severe impairment (CrCl <30 mL/minute).

• Respiratory disease: In general, patients with mild-to-moderate COPD or bronchospastic disease should not receive beta-blockers; if used at all, should be used cautiously with close monitoring. Use is contraindicated in patients with asthma or severe COPD.

• 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 may 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:

• Surgery: May block systemic effects of beta agonists (eg, epinephrine, norepinephrine); notify anesthesiologist if patient is receiving ophthalmic beta blocker therapy. Patients undergoing planned major surgery should be gradually tapered off therapy (if possible) prior to procedure. If necessary during surgery, effects of beta blocker therapy may be reversed by adrenergic agonists.

Monitoring Parameters

Ophthalmic exams and IOP periodically

Pregnancy Risk Factor

C

Pregnancy Considerations

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

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 blurred vision, burning, stinging, itching, eye redness, watery eyes, or change in taste. Have patient report immediately to prescriber signs of vision changes, eye pain, severe eye irritation, bradycardia, shortness of breath, excessive weight gain, swelling of arms or legs, muscle weakness, or signs of a severe sulfonamide reaction (rash; red, swollen, blistered, or peeling skin; red or irritated eyes; mouth, throat, nose, or eye sores; fever, chills, or pharyngitis; cough that is new or worse; loss of strength and energy; any bruising or bleeding; or signs of liver problems like dark urine, fatigue, lack of appetite, nausea or abdominal pain, light-colored stools, vomiting, or jaundice) (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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