Timolol-Dorzolamide-Bimatoprst (timolol maleate/dorzolamide HCl/bimatoprost/PF)

Dosage and concentration of dorzolamide hydrochloride are expressed in terms of dorzolamide.

For the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients, the usual dosage of dorzolamide is 1 drop of a 2% ophthalmic solution in the affected eye(s) 3 times daily.

If the target intraocular pressure (IOP) is not achieved, alternative or additional ocular hypotensive agents may be required. (See Uses: Ocular Hypertension and Glaucoma.) When dorzolamide is used in fixed combination with timolol for the treatment of open-angle glaucoma or ocular hypertension in adults and pediatric patients 2 years of age or older, the usual dosage is 1 drop of an ophthalmic solution containing dorzolamide 2% and timolol 0.5% in the affected eye(s) twice daily. Because of the potential for additive systemic effects, combined use of topical dorzolamide and an oral carbonic anhydrase inhibitor (e.g., acetazolamide, dichlorphenamide, methazolamide) is not recommended by the manufacturer.

Topical dorzolamide has not been evaluated in patients with severe renal impairment (i.e., creatinine clearance less than 30 mL/minute). Because dorzolamide and N-desethyldorzolamide are eliminated principally via renal excretion, the manufacturer states that topical ocular use of the drug in patients with severe renal impairment is not recommended.

Topical dorzolamide has not been evaluated in patients with hepatic impairment, and the manufacturer states that the drug should be used with caution in such patients.

Timolol or timolol maleate is applied topically to the eye as an ophthalmic solution. Timolol maleate also is applied topically to the eye as a gel-forming ophthalmic solution. Timolol maleate also is commercially available in fixed combination with dorzolamide hydrochloride or brimonidine tartrate (as ophthalmic solutions) for topical application to the eye. Care should be taken to avoid contamination of the solution container.

Some timolol ophthalmic solutions contain benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to administration of each dose of these solutions, but may be reinserted 15 minutes after the dose.

Preservative-free ophthalmic solutions containing timolol alone or in fixed combination with dorzolamide should be administered topically to one or both eyes immediately after the single-use container is opened; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.

If the patient is receiving more than one ophthalmic preparation, the preparations should be administered at least 5 minutes apart, although some manufacturers recommend an interval of at least 10 minutes. Containers of timolol maleate ophthalmic gel-forming solution should be inverted and shaken once just prior to administration of each dose. Patients receiving ophthalmic gel-forming solutions of the drug who also are receiving other ophthalmic preparations should be instructed that other topical preparations be administered at least 10 minutes before a dose of the gel-forming solution.

Dorzolamide hydrochloride is applied topically to the eye as an ophthalmic solution. Dorzolamide hydrochloride also is commercially available in fixed combination with timolol maleate for topical application to the eye as an ophthalmic solution.

Care should be taken to avoid contamination of the solution container. (See Cautions: Precautions and Contraindications.)

Dorzolamide ophthalmic solution and some formulations of dorzolamide and timolol ophthalmic solution contain benzalkonium chloride, which may be absorbed by soft contact lenses. Contact lenses should be removed prior to topical application of each dose of these preparations, but may be reinserted 15 minutes after the dose.

Preservative-free dorzolamide and timolol ophthalmic solution in single-use containers should be administered topically to one or both eyes immediately after the container is opened; since sterility cannot be maintained after the individual unit is opened, any remaining contents should be discarded immediately after administration.

If the patient is receiving more than one ophthalmic preparation, the preparations should be administered at least 5 minutes apart.

No dosing information is available for this tab.

No dosing information is available for this tab.

No formal drug interaction studies using bimatoprost have been performed. The manufacturer states that pharmacokinetic interactions are unlikely.

There are no contraindication interactions for this drug.

Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

Agents That Affect Catecholamines/Iobenguane I 123

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with imaging completed with iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores prior to imaging with iobenguane. Before imaging with iobenguane, discontinue agents that affect catecholamines for at least 5 biological half-lives, as clinically tolerated.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine)

Agents That Affect Catecholamines/Iobenguane I 131

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Many compounds that reduce catecholamine uptake or that deplete catecholamine stores may interfere with iobenguane uptake into cells.(1)

CLINICAL EFFECTS: Compounds that reduce catecholamine uptake or that deplete catecholamine stores may impact the dosimetry calculations or effectiveness of iobenguane.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Discuss the use of agents that affect catecholamines. Discontinue drugs that reduce catecholamine uptake or deplete catecholamine stores for at least 5 half-lives before administration of either the dosimetry or a therapeutic dose of iobenguane. Do not administer these drugs until at least 7 days after each iobenguane dose.(1)

DISCUSSION: Many agents may reduce catecholamine uptake or deplete catecholamine stores.(1) Examples include: - CNS stimulants or amphetamines (e.g. cocaine, methylphenidate, dextroamphetamine) - norepinephrine and dopamine reuptake inhibitors (e.g. phentermine) - norepinephrine and serotonin reuptake inhibitors (e.g. tramadol) - monoamine oxidase inhibitors (e.g. phenelzine, linezolid) - central monoamine depleting drugs (e.g. reserpine) - non-select beta adrenergic blocking drugs (e.g. labetalol) - alpha agonists or alpha/beta agonists (e.g. pseudoephedrine, phenylephrine, ephedrine, phenylpropanolamine, naphazoline) - tricyclic antidepressants or norepinephrine reuptake inhibitors (e.g. amitriptyline, bupropion, duloxetine, mirtazapine, venlafaxine) - botanicals that may inhibit reuptake of norepinephrine, serotonin or dopamine (e.g. ephedra, ma huang, St. John's Wort, yohimbine) - calcium channel blockers

Beta-Blockers (Nonselective)/Methyldopa

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Unopposed alpha-adrenergic vasoconstriction produced by alpha-methylnorepinephrine in the presence of beta-blockade.

CLINICAL EFFECTS: Severe hypertension.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Monitor blood pressure during concomitant administration of methyldopa and a nonselective beta-blocker. If hypertension occurs, treatment with phentolamine should be considered.

DISCUSSION: Although methyldopa and propranolol have been used together to treat hypertension, severe increases in blood pressure, including death in one patient, has been reported during administration of these drugs. In addition, methyldopa alone has been reported to cause paradoxical hypertension. Additional studies are needed to define the specific population at risk.

Non-Cardioselective Beta-Blockers/Beta-2 Agonists

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other.

CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm.

PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm.

PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. For timolol ophthalmic drops, counsel patients to apply pressure to the inner corner of the eye after administration to prevent systemic absorption. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure.

DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20)

Non-Cardioselective Beta-Blockers/Salmeterol

SEVERITY LEVEL: 2-Severe Interaction: Action is required to reduce the risk of severe adverse interaction.

MECHANISM OF ACTION: Non-cardioselective beta-blockers and beta-2 agonists may antagonize the effects of each other.

CLINICAL EFFECTS: Diminished response to either the beta-agonist, beta-blocker, or both may occur. Beta-blockers may also induce bronchospasm.

PREDISPOSING FACTORS: Patients receiving beta-2 agonists for the treatment of asthma may be more at risk for bronchospasm.

PATIENT MANAGEMENT: If possible, avoid beta-blocker therapy in asthmatic patients requiring beta-2 agonist therapy. If beta-blocker therapy is required, use a cardio-selective beta-blocker. Monitor patients for decreased effects of either agent, such as increased need for/use of beta-2 agonists or increased heart rate or blood pressure.

DISCUSSION: Many patients with asymptomatic or mild reactive airways disease tolerate beta-blockers well. Most patients with COPD do not have bronchospastic component to their illness and may be given beta-blockers. Heart failure treatment guidelines recommend beta-blockers in the presence of COPD. Non-selective beta-blockers have been shown to have a negative effect on lung function (FEV1) and airway hyperresponsiveness (AHR) in patients with asthma and COPD.(1) An open-label study using the nonselective beta blocker nadolol showed no effect on salbutamol in 10 patients with mild asthma not on controller therapy.(2) A study in 8 healthy men showed that long acting propranolol (160 mg) only effected airway dilation at the 200 mcg salbutamol dose. The 800 mcg and 1600 mcg dose were unaffected. However, penbutolol prevented any significant airway dilation with all doses of salbutamol.(3) In a double blind, three-way, crossover study, 44% (7/16 patients) of patients taking metoprolol showed a greater than 20% decrease in FEV1 compared to 19% (3 patients) after dilevalol and 6% (1 patient) after placebo. Dilevalol and metoprolol significantly inhibited isoproterenol response compared to placebo.(4) A double-blind, randomized, crossover study in 10 asthmatic patients showed that intravenous propranolol produced marked symptomatic bronchoconstriction. Only a slight but significant inhibition of bronchomotor sensitivity to isoproterenol was noted during esmolol infusion.(5) In 18 patients with reversible bronchial asthma, labetalol caused a significant increase in FEV1 and metoprolol caused a significant decrease in FEV1. Concurrent administration of isoproterenol and labetalol caused a further increase in FEV1. The effect of isoproterenol was decreased by metoprolol (100, 200mg).(6) In one study propranolol (0.06mg/kg IV) was shown to almost completely block the effects of isoproterenol in asthmatics. Metoprolol (0.12mg/kg IV) did not affect isoproterenol.(7) Studies have shown that cardioselective beta-blockers are safe for patients with asthma and COPD.(8,9,10) Nebivolol and celiprolol significantly decreased FEV1. Inhalation of albuterol (up to 800mcg) significantly improved FEV1, but the values after nebivolol and celiprolol administration were lower than the initial values.(11) Administration of metoprolol did not cause any respiratory problems in 9 asthmatic patients. There was no significant difference between the metoprolol and placebo groups in the respiratory response to an isoproterenol aerosol in 24 asthmatic patients.(12) Eight male asthmatic patients were given 10 mg bisoprolol, 20 mg bisoprolol, and 100 mg metoprolol. Both bisoprolol and metoprolol caused bronchoconstriction measured by a significant fall in PEFR (peak expiratory flow rate). Terbutaline was able to reverse bronchoconstriction in all patients.(13) A double blind, placebo-controlled study analyzed the use of atenolol 100mg, metoprolol 100mg, or acebutolol 400 mg in 8 asthmatic patients before and after exercise. All three drugs reduced significantly FEV1 and PEFR. Administration of terbutaline improved all respiratory indices.(14) A double-blind crossover trial in 10 asthmatic patients showed that a single IV dose of atenolol 3mg caused slight impairment of ventilatory function. A dose of salbutamol by inhalation was able to reverse the bronchial effect of atenolol.(15) Propranolol (80mg/day), oxprenolol (80mg/day), atenolol (100mg/day), and celiprolol 200mg/day were given to 10 asthmatic patients in a randomized, crossover design with a two week washout period between each drug. The non-beta 1 selective beta blockers (propranolol, oxprenolol) caused a significant reduction in FEV1 and inhibited the bronchodilator response to inhaled salbutamol. Atenolol and celiprolol (beta1 selective beta blockers) did not significantly affect respiratory function or antagonize salbutamol effects.(16) A double blind, randomized, within patient, placebo-controlled study compared the cardioselective beta-blocker atenolol to the non-selective propranolol. Atenolol caused a significantly less drop in FEV1 compared to propranolol. The effect of isoprenaline plus the beta blockers were also studied. Both atenolol and propranolol effected isoprenaline FEV1 dose response curves but the greatest displacement was seen with propranolol.(17) The pulmonary effects of celiprolol 200 mg, celiprolol 400mg, propranolol 40mg, atenolol 100 mg were evaluated in 34 asthmatic patients. Propranolol and atenolol caused significant reductions in pulmonary function. Propranolol pretreatment caused a significant reduction in the effect of the bronchodilator. Celiprolol did not antagonize the bronchodilators.(18) A double-blind, placebo controlled, randomized, crossover design study studied the effects of propranolol 80mg or celiprolol 200 or 400mg on pulmonary function. Propranolol produced a significant decrease in FEV1 and FVC. Celiprolol and placebo had similar results. The effect of aerosolized terbutaline was also measured. Even at supratherapeutic doses, terbutaline was unable to restore pulmonary function parameters to baseline levels after treatment with propranolol. Terbutaline caused further bronchodilation after administration of celiprolol.(19) Eleven asthmatic patients showed significant bronchoconstriction in small airways after propranolol 40mg and pindolol 2.5mg in a double blind, randomized trial. Large airways only showed bronchoconstriction with propranolol. Terbutaline 0.5mg subcutaneous was given after pretreatment with propranolol and pindolol. The bronchodilator effect of terbutaline on large airways was diminished after both propranolol and timolol.(20)

Moderate Interaction: Assess the risk to the patient and take action as needed.

Beta-Blockers/Clonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Withdrawal of clonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of clonidine in patients receiving both clonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: In a patient receiving both drugs, discontinuation of the beta-blocker prior to clonidine may decrease the occurrence of rebound hypertension. If clonidine is discontinued first, rebound hypertension can be treated by restarting the clonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing clonidine withdrawal, although conflicting reports exist. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

DISCUSSION: Increased blood pressure has been observed in patients following: 1) the discontinuation of clonidine in patients receiving beta-blockers, 2) the replacement of clonidine therapy with beta-blockers, 3) the simultaneous discontinuation of both drugs. Conflicting reports exist on the development of increased blood pressure after clonidine withdrawal in patients receiving labetalol. Patients receiving labetalol who are being withdrawn from clonidine should still be closely monitored.

Beta-Blockers/Moxonidine

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Withdrawal of moxonidine triggers increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

CLINICAL EFFECTS: Severe hypertension may occur upon abrupt discontinuation of moxonidine in patients receiving both moxonidine and beta-blockers. In addition, concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: If combination therapy with moxonidine and a beta-blocker is to be ceased, the beta-blocker should be stopped first to decrease the risk of rebound hypertension. Moxonidine may be stopped after a few days have elapsed. During cessation of therapy blood pressure should be regularly monitored. If moxonidine is discontinued first, rebound hypertension can be treated by restarting the moxonidine or by the IV administration of phentolamine, phenoxybenzamine or prazosin. Since labetalol has both alpha and beta activity, administration of labetalol may prevent rebound hypertension in patients undergoing moxonidine withdrawal, although conflicting reports exist. When adding either of these agents to the drug regimen of the patient, monitor blood pressure. Concurrent use is expected to produce additive effects on blood pressure and heart rate requiring standard monitoring precautions.

DISCUSSION: Abrupt cessation of combination therapy with moxonidine and a beta-blocker may result in rebound hypertension. Withdrawal of moxonidine may trigger increased catecholamine release. Beta-blockers inhibit the vasodilation mediated by the beta 2 receptor, leaving the vasoconstriction mediated by the alpha 2 receptor unopposed.

Dorzolamide/Carbonic Anhydrase Inhibitors

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Dorzolamide and other carbonic anhydrase inhibitors cause a decrease in aqueous humor secretion by slowing the formation of bicarbonate ions with a subsequent reduction of sodium and fluid transport which results in a reduction of intraocular pressure.(1)

CLINICAL EFFECTS: If dorzolamide is given with other carbonic anhydrase inhibitors it may cause electrolyte disturbances, because dorzolamide can be absorbed systemically.(1)

PREDISPOSING FACTORS: Patients with conditions that predispose to acidosis (such as renal disease, severe respiratory disorders, status epilepticus, diarrhea, and being on a ketogenic diet) may be at increased risk of experiencing adverse effects from concurrent carbonic anhydrase inhibitors.

PATIENT MANAGEMENT: The manufacturer of dorzolamide states that concurrent use with oral carbonic anhydrase inhibitors is not recommended.(1)

DISCUSSION: Although no human data is available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following administration of dorzolamide and oral carbonic anhydrase inhibitors.(1)

Iop-Lowering Prostaglandin Analogs/Bimatoprost Topical

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: When used ophthalmically to lower intraocular pressure, prostaglandin analogs may be at the top of the dose-response curve. Use of an additional prostaglandin may result in decreased effectiveness.(1)

CLINICAL EFFECTS: Concurrent use of topical bimatoprost may result in decreased effectiveness of ophthalmic prostaglandin analogs and an increase in intraocular pressure.(1)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Patients using ophthalmic prostaglandin analogs to lower intraocular pressure should be monitored for changes in their intraocular pressure.(1) Use of topical bimatoprost may need to be discontinued in patients who stop responding to their ophthalmic prostaglandin analogue.

DISCUSSION: Studies have shown that the ophthalmic administration of bimatoprost twice daily is less effective at lowering intraocular pressure than ophthalmic bimatoprost administered once daily. Concurrent use of topical bimatoprost may decrease the effectiveness of ophthalmic prostaglandin analogs.(1)

Selected Beta-Blockers/Selected Alpha-Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Alpha-blockers may cause syncope with sudden loss of consciousness secondary to excessive postural hypotension. Following the first dose of an alpha-blocker, compensatory tachycardia helps to prevent or limit syncope. Beta-blockers may inhibit this tachycardia, thereby worsening alpha-blocker induced hypotension.

CLINICAL EFFECTS: The hypotensive effects of an alpha-blocker may be increased in patients on concurrent beta-blocker therapy.

PREDISPOSING FACTORS: Patients may be at increased risk of postural hypotension with concurrent diuretic therapy and those on low-sodium diets.

PATIENT MANAGEMENT: When starting alpha-blocker therapy in patients receiving beta-blockers, consider initiating treatment with a reduced dose of the alpha-blocker. If syncope occurs, provide supportive treatment as necessary. The adverse effect is self limiting and in most cases does not recur after the initial period of therapy or during subsequent dose titration with the alpha-blocker.

DISCUSSION: Beta-blockers increase the acute postural hypotension that frequently follows the first dose of an alpha-blocker. Initiation of beta-blocker therapy in patients that have started taking an alpha-blocker would not be expected to produce acute postural hypotension. Alpha-blockers linked to this interaction include alfuzosin, doxazosin, prazosin, and terazosin. Beta-blockers linked to this interaction include acebutolol, atenolol, betaxolol, bevantolol, levobunolol, metoprolol, nadolol, pindolol, pronethalol, propranolol, and timolol.

Selected Beta-Blockers/Selected Calcium Channel Blockers

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Synergistic pharmacologic activity.

CLINICAL EFFECTS: May see an increase in the therapeutic and toxic effects of both drugs. Concurrent use in patients with low heart rates may unmask sick sinus syndrome.

PREDISPOSING FACTORS: Preexisting left ventricular dysfunction and high doses of the beta-blocking agent may predispose patients to adverse responses to this drug combination. Other possible factors include parenteral administration and concurrent administration of other cardio-depressant drugs such as antiarrhythmics.

PATIENT MANAGEMENT: Monitor the patient for signs of increased cardio-depressant effects and hypotension. Adjust the dose accordingly.

DISCUSSION: Coadministration of these classes of drugs may be effective in the treatment of angina pectoris and hypertension. Patients should be screened in order to determine who should receive this combination of agents. The concurrent use of mibefradil and beta-blockers in patients with low heart rates may unmask underlying sick sinus syndrome. One or more of the drug pairs linked to this monograph have been included in a list of interactions that could be considered for classification as "non-interruptive" in EHR systems. This DDI subset was vetted by an expert panel commissioned by the U.S. Office of the National Coordinator (ONC) for Health Information Technology.

Selected Beta-Blockers/Theophyllines

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Certain beta-blockers may inhibit theophylline metabolism. In addition, beta-blockers, especially non-selective agents, can antagonize the pharmacologic effects of theophylline.

CLINICAL EFFECTS: Even though theophylline concentrations may increase leading to increased possibility of theophylline toxicity, beta-blockers decrease theophylline's therapeutic effects.

PREDISPOSING FACTORS: Cigarette smoking may exacerbate this interaction.

PATIENT MANAGEMENT: Avoid the use of non-selective beta-blockers with theophylline. If a beta-blocker must be used, a cardioselective agent that does not decrease the clearance of theophylline (e.g., atenolol) should be considered. However, since cardioselectivity is not absolute and is less selective at higher doses, cardioselective beta-blockers should be used with caution in patients with bronchospastic disease.

DISCUSSION: Inhibition of theophylline metabolism is greatest with lipophilic beta-blockers undergoing hepatic metabolism (e.g., propranolol). Additionally, the decrease in theophylline clearance appears to be dose dependent as the higher the beta-blocker dose, the greater the decrease in theophylline clearance. If the patient is on both drugs and the beta-blocker is discontinued, serum theophylline concentrations may decrease. In these cases, monitor for a decrease in theophylline therapeutic effect and adjust the dose as needed.

Slt Ophth Non-Cardioselective Beta-Blockers/Antidiabetics

SEVERITY LEVEL: 3-Moderate Interaction: Assess the risk to the patient and take action as needed.

MECHANISM OF ACTION: Not fully established. Probably blockade of a variety of beta-adrenergic responses to hypoglycemia.(1,2)

CLINICAL EFFECTS: Diminished response to sulfonylureas and insulin may occur. Frequency and severity of hypoglycemic episodes may be increased, while warning symptoms of low blood sugar may be masked.(1,2)

PREDISPOSING FACTORS: None determined.

PATIENT MANAGEMENT: Try to avoid beta-blocker therapy, particularly in diabetics prone to hypoglycemic attacks. One of the cardioselective agents may decrease risk of hypertensive attacks and allow more rapid glucose recovery from hypoglycemia. Patients should be counseled not to rely on tachycardia to diagnose hypoglycemia, since it is masked by beta-blocker therapy. Diaphoresis is unaffected by beta-blockade and can be used by the diabetic to recognize hypoglycemia.

DISCUSSION: A double blind, randomized, 12 month study of 39 patients tested the metabolic effects of pindolol (5mg BID) compared to control group on insulin sensitivity. The patient's insulin sensitivity index decreased 17% when on pindolol treatment compared to placebo (p<0.01). Insulin mediated glucose uptake was significantly lower (p<0.05) with propranolol treatment than with placebo.(3) A study of 26 patients with chronic heart failure showed that carvedilol (average daily dose 27.5mg/d) caused a significant decrease in fasting insulin levels (17.09 to 10.77 microU/ml, p <0.05) compared to pre-treatment levels. This trial also showed that patients on carvedilol had significantly (p=0.015) lower fasting insulin levels (10.77 microU/ml) compared to the fasting insulin levels (20.72 microU/ml) of patients on bisoprolol treatment (5.9mg/d).(4) There have been case reports of hypoglycemia following the addition of ophthalmic timolol to a diabetic regimen.(5-7) Studies have shown that ophthalmic beta-blockers, especially the aqueous solution, have significant systemic absorption and do not undergo first-pass metabolism.(8,9)

Bimatoprost is contraindicated in patients with known hypersensitivity to the drug or any ingredient in the formulation.

• Acute decompensated heart failure
• Asthma
• Cardiogenic shock
• Complete atrioventricular block
• Incomplete AV heart block
• Sinus bradycardia

• Aphakia
• Chronic obstructive pulmonary disease
• Cystoid macular edema
• Hyperthyroidism
• Iritis
• Uveitis

• Diabetes mellitus
• Hypoglycemic disorder
• Myasthenia gravis
• No disease contraindications

Conjunctival hyperemia, growth of eyelashes, and ocular pruritus occurred in approximately 15-45% of patients who received bimatoprost 0.03% ophthalmic solution for reduction of IOP in clinical trials. Approximately 3% of patients discontinued therapy because of conjunctival hyperemia. Ocular dryness, visual disturbance, ocular burning, foreign body sensation, ocular pain, pigmentation of the periocular skin, blepharitis, cataract, superficial punctate keratitis, periorbital erythema, ocular irritation, and eyelash darkening have been reported in approximately 3-10% of patients who received bimatoprost 0.03% ophthalmic solution in clinical trials. Adverse ocular effects reported in approximately 1-3% of patients include ocular discharge, tearing, photophobia, allergic conjunctivitis, asthenopia, increases in iris pigmentation, and conjunctival edema. Adverse systemic events reported in approximately 1-10% of patients include infection (primarily colds and upper respiratory tract infections), headache, abnormal liver function test results, asthenia, and hirsutism.

Conjunctival hyperemia was reported in 31% of patients who received bimatoprost 0.01% ophthalmic solution for reduction of IOP in clinical trials. Approximately 1.6% of patients discontinued therapy because of conjunctival hyperemia. Conjunctival edema, conjunctival hemorrhage, eye irritation, ocular pain, ocular pruritus, eyelid erythema, eyelid pruritus, growth of eyelashes, hypertrichosis, instillation site irritation, punctate keratitis, skin hyperpigmentation, blurred vision, and decreased visual acuity were reported in 1-4% of patients who received bimatoprost 0.01% ophthalmic solution.

The most common adverse reactions reported during clinical trials in patients receiving bimatoprost 0.03% ophthalmic solution applied to the skin of the upper eyelid margins to increase eyelash growth include ocular pruritus, conjunctival hyperemia, and skin hyperpigmentation, each reported in approximately 3-4% of patients. Ocular irritation, dry eye symptoms, periorbital erythema, foreign body sensation, abnormal hair growth, and iris hyperpigmentation also were reported.

More Frequent

• Ocular itching

Less Frequent

• Cataracts
• Conjunctivitis
• Eyelid erythema
• Infection
• Ocular pain
• Punctate keratitis
• Visual changes

Rare or Very Rare

• Abnormal hepatic function tests
• Acute myocardial infarction
• Acute respiratory failure
• Agranulocytosis
• Allergic conjunctivitis
• Anaphylaxis
• Angioedema
• Angioedema
• Aplastic anemia
• Bacterial keratitis
• Bradycardia
• Bronchospastic pulmonary disease
• Bronchospastic pulmonary disease
• Cardiac arrhythmia
• Cerebrovascular accident
• Chemosis
• Choroidal detachment
• Choroidal detachment
• Contact dermatitis
• Cystoid macular edema
• Cystoid macular edema
• Decreased corneal sensitivity
• Dyspnea
• Epistaxis
• General weakness
• Heart block
• Heart failure
• Hepatic necrosis
• Hypersensitivity drug reaction
• Hypertension
• Hypertension
• Hypotension
• Iridocyclitis
• Iris hyperpigmentation
• Iritis
• Keratitis
• Muscle weakness
• Myopia
• Ocular inflammation
• Ocular pain
• Paresthesia
• Peyronie's disease
• Skin rash
• Sore throat
• Stevens-johnson syndrome
• Systemic lupus erythematosus
• Toxic epidermal necrolysis
• Urolithiasis

More Frequent

• Conjunctival hyperemia
• Dry eye
• Dysgeusia
• Eyelid erythema
• Hirsutism
• Hyperpigmentation of eyelid
• Hypertrichosis of eyelid eyelashes
• Ocular irritation
• Ocular irritation
• Ocular itching
• Ocular itching
• Punctate keratitis

Less Frequent

• Blepharitis
• Blurred vision
• Blurred vision
• Conjunctivitis
• Dizziness
• Dry eye
• Eye tearing
• Foreign body sensation of eye
• Headache disorder
• Ocular discharge
• Ocular pain
• Ocular redness
• Photophobia
• Upper respiratory infection

Rare or Very Rare

• Acute cognitive impairment
• Allergic dermatitis
• Alopecia
• Angina
• Anorexia
• Asthenopia
• Behavioral disorders
• Blepharitis
• Blepharoptosis
• Blepharoptosis
• Blurred vision
• Chest pain
• Cough
• Deepening of upper eyelid sulcus
• Delirium
• Depression
• Diarrhea
• Diplopia
• Dizziness
• Dizziness
• Drowsy
• Dry eye
• Dry skin
• Dyspepsia
• Dyspnea
• Dysuria
• Enophthalmos
• Erectile dysfunction
• Erythema
• Eye tearing
• Eye tearing
• Eyelid crusting
• Eyelid edema
• Fatigue
• Foreign body sensation of eye
• General weakness
• General weakness
• Hallucinations
• Headache disorder
• Headache disorder
• Hordeolum
• Hypotrichosis of eyelid lashes
• Insomnia
• Libido changes
• Madarosis of eyelid
• Memory impairment
• Nasal congestion
• Nausea
• Nausea
• Nausea
• Nervousness
• Nightmares
• Ocular discharge
• Ocular irritation
• Ocular redness
• Palpitations
• Paresthesia
• Periorbital edema
• Photophobia
• Pruritus of skin
• Psoriasiform eruption
• Raynaud's phenomenon
• Sensation of cold
• Skin pigmentation enhancement
• Skin rash
• Symptoms of anxiety
• Tinnitus
• Trichiasis
• Trichorrhexis of eyelashes
• Urticaria
• Vertigo
• Visual changes
• Vomiting
• Xerostomia
• Xerostomia

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Use of bimatoprost for the treatment of open-angle glaucoma or ocular hypertension in pediatric patients younger than 16 years of age is not recommended because of potential safety concerns related to increased pigmentation following long-term use. (See Pigmentation under Cautions: Warnings/Precautions.)

In a randomized, double-blind, vehicle-controlled study in 71 pediatric patients 5-17 years of age with hypotrichosis, topical application of bimatoprost 0.03% to the upper eyelid margins once daily for 16 weeks was associated with improvement in overall eyelash prominence, as measured by an increase of at least one grade on the 4-point Global Eyelash Assessment (GEA) scale from baseline to week 16, in 73% of adolescents with hypotrichosis not associated with a contributory medical condition and 85 or 44% of pediatric patients with hypotrichosis caused by chemotherapy or associated with alopecia areata, respectively; response rates for vehicle recipients with these respective conditions were 7, 100, and 33%. No new safety concerns were identified in this study.

In developmental studies in animals, bimatoprost exposure was compared with the human exposure following once-daily, bilateral, topical administration of bimatoprost 0.3% to the eyes (cornea or conjunctival sac). Abortion or early delivery was observed in mice and rats at exposure levels of at least 33 and 94 times human exposure but not at exposure levels of 2.6 and 47 times human exposure, respectively. Reduced gestation period, reduced fetal body weight, and increased fetal and pup mortality were observed in rats at exposures levels of at least 41 times human exposure. No adverse effects were observed in rat offspring at exposures estimated at 14 times human exposure.

There are no adequate and well-controlled studies using bimatoprost in pregnant women. Postmarketing experience has revealed no increase in the risk of major birth defects or spontaneous abortions. Bimatoprost should be used during pregnancy only if the potential benefits justify the possible risk to the fetus.

Reproduction studies in mice, rats, and rabbits using oral timolol dosages up to 50 mg/kg daily (7000 times the systemic exposure following the maximum recommended human ophthalmic dosage) have not revealed evidence of harm to the fetus. Although delayed fetal ossification was observed at this dosage in rats, no adverse effects on postnatal development occurred in this species. Oral timolol dosages of 1 g/kg daily (142,000 times the systemic exposure following the maximum recommended human ophthalmic dosage) were maternotoxic and resulted in an increased number of fetal resorptions in mice. Increased fetal resorptions were also observed in rabbits receiving oral timolol dosages 14,000 times the systemic exposure following the maximum recommended human ophthalmic dosage.

There are no adequate and controlled studies to date using timolol ophthalmic solution in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Reproduction studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 37 times higher than the lower limit of detection in human plasma following ocular administration revealed malformations of the vertebral bodies. These malformations occurred at dosages that caused metabolic acidosis and decreased body weight gain in dams and decreased fetal weight. Reproductive studies in rabbits using oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 15 times higher than the lower limit of detection in human plasma following ocular administration did not reveal evidence of teratogenic effects or embryotoxicity.

There are no adequate and controlled studies to date using dorzolamide in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

It is not known whether bimatoprost is distributed into human milk following topical application to the eye. Bimatoprost is distributed into milk in rats following IV administration at a dose equivalent to 324 times the recommended human ocular dose of bimatoprost 0.03%; animal data are lacking at clinically relevant doses. The developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for bimatoprost and any potential adverse effects of the drug on the breast-fed infant.

Timolol is distributed into milk following oral or topical ophthalmic administration. Because of the potential for serious adverse reactions from timolol in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

In lactating rats given oral dorzolamide at dosages that resulted in estimated peak plasma concentrations that were 52 times higher than the lower limit of detection in human plasma following ocular administration, decreases of 5-7% in body weight gain in offspring and developmental delay (i.e., incisor eruption, vaginal canalization, eye opening) secondary to lower fetal body weight have been reported.

It is not known whether dorzolamide is distributed into human milk. Because of the potential for serious adverse reactions to dorzolamide in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

No overall differences in safety and efficacy have been observed between geriatric patients and younger adults.