Drug Interaction Report

MONITOR: Many psychotherapeutic and CNS-active agents (e.g., anxiolytics, sedatives, hypnotics, antidepressants, antipsychotics, opioids, alcohol, muscle relaxants) exhibit hypotensive effects, especially during initiation of therapy and dose escalation. Coadministration with antihypertensives and other hypotensive agents, in particular vasodilators and alpha-blockers, may result in additive effects on blood pressure and orthostasis.

MANAGEMENT: Caution and close monitoring for development of hypotension is advised during coadministration of these agents. Some authorities recommend avoiding alcohol in patients receiving vasodilating antihypertensive drugs. Patients should be advised to avoid rising abruptly from a sitting or recumbent position and to notify their physician if they experience dizziness, lightheadedness, syncope, orthostasis, or tachycardia.

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MONITOR: Fluoxetine may increase plasma alprazolam concentrations, decrease alprazolam clearance, and increase the elimination half-life of alprazolam. The mechanism may be related to inhibition of CYP450 3A4 microsomal drug metabolism. This combination may impair psychomotor performance and reports have suggested that the risk of cardiac toxicity such as bradycardia may be increased.

MANAGEMENT: If fluoxetine and alprazolam must be used together, close observation is recommended for increased adverse effects. Patients should be warned about excessive drowsiness and potential adverse effects on their psychomotor and driving skills.

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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: The efficacy of anticonvulsants may be diminished during coadministration with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitor (SNRIs). Antidepressants including SSRIs and SNRIs can reduce seizure threshold. In clinical trials, convulsions have typically been reported in 0.1% to 0.3% of patients receiving SSRIs for major depressive disorders. There have been rare reports of prolonged seizures in patients on fluoxetine receiving electroconvulsive therapy (ECT).

MONITOR: Coadministration of SSRIs or SNRIs may potentiate the central nervous system (CNS) adverse effects of anticonvulsants such as somnolence and cognitive and psychomotor impairment.

MONITOR: Coadministration of SSRIs or SNRIs with some anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and valproic acid, may increase the risk of hyponatremia. Treatment with SSRIs or SNRIs has been associated with hyponatremia, which may be due to the syndrome of inappropriate antidiuretic hormone secretion (SIADH) in many cases. While generally reversible following discontinuation of SSRI/SNRI treatment, cases with serum sodium lower than 110 mmol/L have been reported. Hyponatremia and SIADH may also result from treatment with some anticonvulsants. The risk appears to be dose-related, and elderly patients and patients who are volume depleted (e.g., diuretic use) may be at greater risk.

MANAGEMENT: SSRIs and SNRIs should be avoided in patients with unstable epilepsy, and used cautiously in patients with epilepsy controlled with anticonvulsant medications. Treatment with SSRIs and SNRIs should be discontinued if seizures develop or seizure frequency increases. Patients receiving SSRIs or SNRIs with anticonvulsants, particularly carbamazepine, eslicarbazepine, oxcarbazepine and/or valproic acid, should also have serum sodium levels measured regularly and monitored for development of hyponatremia, particularly when higher dosages of these medications are used. Signs and symptoms of hyponatremia include nausea, vomiting, headache, difficulty concentrating, memory impairment, confusion, malaise, lethargy, muscle weakness or spasms, and unsteadiness. In more severe and/or acute cases, hallucination, syncope, seizure, coma, respiratory arrest, and death may occur. Discontinuation of SSRIs and SNRIs should be considered in patients who develop symptomatic hyponatremia, and appropriate medical intervention instituted. All patients receiving concomitant therapy with SSRIs or SNRIs and anticonvulsants should be counseled against driving, operating machinery, or engaging in potentially 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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GENERALLY AVOID: The pharmacologic activity of oral midazolam, triazolam, and alprazolam may be increased if taken after drinking grapefruit juice. The proposed mechanism is CYP450 3A4 enzyme inhibition. In addition, acute alcohol ingestion may potentiate CNS depression and other CNS effects of many benzodiazepines. Tolerance may develop with chronic ethanol use. The mechanism may be decreased clearance of the benzodiazepines because of CYP450 hepatic enzyme inhibition. Also, it has been suggested that the cognitive deficits induced by benzodiazepines may be increased in patients who chronically consume large amounts of alcohol.

MANAGEMENT: The manufacturer recommends that grapefruit juice should not be taken with oral midazolam. Patients taking triazolam or alprazolam should be monitored for excessive sedation. Alternatively, the patient could consume orange juice which does not interact with these drugs. Patients should be advised to avoid alcohol during benzodiazepine therapy.

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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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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GENERALLY AVOID: Alcohol may potentiate some of the pharmacologic effects of CNS-active agents. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Patients receiving CNS-active agents should be warned of this interaction and advised to avoid or limit consumption of alcohol. Ambulatory patients should be counseled to avoid hazardous activities requiring complete 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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GENERALLY AVOID: The concurrent use of ethanol and alpha-1 adrenergic blockers may cause increased hypotensive effects. Patients with aldehyde dehydrogenase deficiencies (primarily Asians) may be at a higher risk of this interaction. The mechanism has not been determined. Data exist for prazosin and other alpha adrenergic blockers are expected to interact also. In addition, any patients taking alpha adrenergic blockers may experience excessive orthostatic hypotension with ethanol ingestion, due to ethanol's unopposed vasodilatory effects in the presence of alpha adrenergic blockade.

MANAGEMENT: Patients who develop a flushing reaction after ethanol ingestion (indicates a possible aldehyde dehydrogenase deficiency) should be advised to avoid ethanol or limit their intake. All patients should be warned about the possibility of orthostatic hypotension with concurrent ethanol use.

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