Drug Interactions between brimonidine / dorzolamide / latanoprost / timolol ophthalmic and Theraflu Warming Relief Nighttime Multi-Symptom Cold Caplets

MONITOR: Central nervous system- and/or respiratory-depressant effects may be additively or synergistically increased in patients taking multiple drugs that cause these effects, especially in elderly or debilitated patients. Sedation and impairment of attention, judgment, thinking, and psychomotor skills may increase.

MANAGEMENT: During concomitant use of these drugs, patients should be monitored for potentially excessive or prolonged CNS and respiratory depression. Cautious dosage titration may be required, particularly at treatment initiation. Ambulatory patients should be counseled to avoid hazardous activities requiring mental alertness and motor coordination until they know how these agents affect them, and to notify their physician if they experience excessive or prolonged CNS effects that interfere with their normal activities.

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MONITOR: Coadministration with inhibitors of CYP450 2D6 may increase the systemic effects of topically administered timolol, which is metabolized by the isoenzyme. Following ocular administration, timolol is systemically absorbed and can reach plasma levels associated with adverse beta-adrenergic blocking effects such as bronchospasm, depression, bradycardia, and hypotension. The risk may be increased if clearance of the drug is significantly diminished by concomitant CYP450 2D6 inhibitors. In one case report, a 70-year-old man experienced dizziness secondary to sinus bradycardia after 12 weeks of treatment with a 0.5% timolol eye drop while also taking quinidine sulfate 500 mg three times a day. The symptoms subsided and sinus rhythm returned to normal a day after discontinuation of both drugs. However, symptoms returned within 30 hours after restarting both drugs a month later. Quinidine was discontinued, and the patient did not experience further problems. In a study of 13 healthy volunteers, extensive metabolizers of CYP450 2D6 administered quinidine (50 mg single oral dose) 30 minutes before 0.5% timolol eye drop (2 drops in each nostril) demonstrated significantly greater reductions in exercise heart rate and had higher plasma timolol concentrations than when given timolol alone. The changes resulted in values that were similar to those observed in poor metabolizers given the timolol eye drop without quinidine. In another study, 12 healthy volunteers given cimetidine (400 mg orally twice a day for 7 doses) and 0.5% timolol eye drop (0.05 mL in each eye 30 minutes after last dose of cimetidine) demonstrated additional reductions in resting heart rate and intraocular pressure relative to administration of the timolol eye drop alone, although there were no additional reductions of exercise heart rate or systolic blood pressure (at rest or after exercise) compared to timolol alone.

MANAGEMENT: Patients should be monitored for systemic beta-adrenergic blocking effects of topical timolol during coadministration with CYP450 2D6 inhibitors such as cimetidine, quinidine, and certain selective serotonin reuptake inhibitors. Particular caution is warranted in elderly patients, since they are generally more susceptible to adverse effects of topically administered beta blockers.

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MONITOR: A case report suggests that beta-blockers may enhance the pressor response to phenylephrine. The proposed mechanism involves blockade of beta-2 adrenergic receptors in the peripheral vasculature, resulting in unopposed alpha-adrenergic effect of phenylephrine that is responsible for vasoconstriction. Additionally, beta-blockers may desensitize baroreceptors that normally modulate heart rate in response to blood pressure elevations by increasing vagal activity on the sinoauricular node. In the case report, a woman with a history of hypertension treated with hydrochlorothiazide (50 mg twice a day) and propranolol (40 mg four times a day) developed sudden bitemporal pain and became unconscious shortly after she was given one drop of a 10% phenylephrine solution in each eye during an ophthalmic examination. She subsequently died of intracerebral hemorrhage due to rupture of a berry aneurysm. The authors noted that the patient had received the same eye drop without incident on two previous occasions when she was not receiving blood pressure or other medications. Nevertheless, an interaction between phenylephrine and beta-blockers is not well established. Phenylephrine acts predominantly on alpha-adrenergic receptors and has little or no direct effect on beta-2 adrenergic receptors, although it may affect them indirectly by enhancing release of norepinephrine from adrenergic nerve terminals. In a study of 12 patients with hypertension, mean phenylephrine doses required to increase systolic blood pressure by 25 mmHg were not significantly different following 2 weeks on propranolol, metoprolol, and placebo (4.8 mcg/kg, 4.7 mcg/kg, and 5.3 mcg/kg, respectively). Baroreceptor-mediated decreases in heart rate during phenylephrine infusion were also in the same range on propranolol, metoprolol, and placebo over baseline heart rate values. In another study, no changes in blood pressure or heart rate were observed in hypertensive patients treated with metoprolol who were given 0.5 to 4 mg doses of phenylephrine intranasally every hour up to a total of 7.5 to 15 mg, or 4 to 30 times the usual recommended dose, compared to placebo or baseline values. These results support the lack of a significant interaction between beta-blockers and phenylephrine.

MANAGEMENT: Until more information is available, caution should be exercised when phenylephrine is used in combination with beta-blockers including ophthalmic formulations, which may be systemically absorbed and can produce clinically significant systemic effects even at low or undetectable plasma levels. Monitoring of blood pressure should be considered, particularly when phenylephrine is administered intravenously or intraocularly. Although an interaction is not likely to occur with cardioselective beta-blockers, caution may be advisable when high dosages are used, since cardioselectivity is not absolute and may be lost with larger doses. A beta-blocker such as propranolol may be used to treat cardiac arrhythmias that occur during administration of phenylephrine.

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MONITOR: Topically administered alpha-2 adrenergic receptor agonists such as apraclonidine and brimonidine are systemically absorbed, with the potential for producing rare but clinically significant systemic effects. Although the interaction has not been specifically studied, the possibility of an additive or potentiating effect with central nervous system (CNS) depressants such as alcohol, barbiturates, opiates, anxiolytics, sedatives, and anesthetics should be considered. Additive hypotensive effects and orthostasis may also occur with some CNS depressants and other agents that have these effects, particularly during initial dosing and/or parenteral administration.

MANAGEMENT: Patients receiving topical alpha-2 adrenergic receptor agonists in combination with agents that can cause CNS depression should be made aware of the potential for increased adverse effects such as drowsiness, dizziness, lightheadedness and confusion, and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should also avoid rising abruptly from a sitting or recumbent position and notify their physician if they experience orthostasis or tachycardia.

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MONITOR: Topically administered alpha-2 adrenergic receptor agonists such as apraclonidine and brimonidine are systemically absorbed, with the potential for producing rare but clinically significant systemic effects. Although the interaction has not been specifically studied, the possibility of an additive or potentiating effect with central nervous system (CNS) depressants such as alcohol, barbiturates, opiates, anxiolytics, sedatives, and anesthetics should be considered. Additive hypotensive effects and orthostasis may also occur with some CNS depressants and other agents that have these effects, particularly during initial dosing and/or parenteral administration.

MANAGEMENT: Patients receiving topical alpha-2 adrenergic receptor agonists in combination with agents that can cause CNS depression should be made aware of the potential for increased adverse effects such as drowsiness, dizziness, lightheadedness and confusion, and counseled to avoid activities requiring mental alertness until they know how these agents affect them. Patients should also avoid rising abruptly from a sitting or recumbent position and notify their physician if they experience orthostasis or tachycardia.

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MONITOR: Topically administered alpha-2 adrenergic receptor agonists such as apraclonidine and brimonidine are systemically absorbed, with the potential for producing rare but clinically significant systemic effects such as hypotension and bradycardia. The possibility for an additive or potentiating effect on blood pressure and heart rate should be considered when used with other medications that affect these parameters, such as ophthalmic and systemic beta blockers, vasodilators, cardiac glycosides, and antihypertensive agents.

MANAGEMENT: Blood pressure and pulse rate should be monitored regularly when topical alpha-2 adrenergic receptor agonists are prescribed in combination with cardiovascular drugs. Patients should be advised to notify their physician if they experience slow pulse, irregular heartbeat, dizziness, lightheadedness, or syncope.

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