Drug Interaction Report

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: 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: 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: 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: Centrally-acting anticholinergic agents may antagonize the therapeutic effects of neuroleptic agents. Although these drugs have been used together clinically, the possibility of increased risk of adverse effects such as central nervous system depression and tardive dyskinesia should also be considered. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. In hot weather, the risk of hyperthermia and heat stroke should be considered, as neuroleptic agents can interfere with temperature regulation in the hypothalamus while anticholinergic agents tend to inhibit peripheral sweating mechanisms.

MANAGEMENT: Caution is advised if anticholinergic agents are used with neuroleptic agents, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Prophylactic administration of anticholinergic agents is sometimes given clinically during neuroleptic therapy for drug-induced parkinsonism or extrapyramidal symptoms but may not always be appropriate. Patients prescribed this combination should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop. During hot weather, patients should avoid prolonged sun exposure and intense physical exertion and maintain adequate fluid intake.

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MONITOR: Centrally-acting anticholinergic agents may antagonize the therapeutic effects of neuroleptic agents. Although these drugs have been used together clinically, the possibility of increased risk of adverse effects such as central nervous system depression and tardive dyskinesia should also be considered. In addition, excessive anticholinergic effects may occur in combination use, which can result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of anticholinergic intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. In hot weather, the risk of hyperthermia and heat stroke should be considered, as neuroleptic agents can interfere with temperature regulation in the hypothalamus while anticholinergic agents tend to inhibit peripheral sweating mechanisms.

MANAGEMENT: Caution is advised if anticholinergic agents are used with neuroleptic agents, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Prophylactic administration of anticholinergic agents is sometimes given clinically during neuroleptic therapy for drug-induced parkinsonism or extrapyramidal symptoms but may not always be appropriate. Patients prescribed this combination should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A dosage reduction in one or both drugs may be necessary if excessive adverse effects develop. During hot weather, patients should avoid prolonged sun exposure and intense physical exertion and maintain adequate fluid intake.

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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: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of intoxication commonly include mydriasis, blurred vision, flushed face, fever, dry skin and mucous membranes, tachycardia, urinary retention, and constipation. Central symptoms may include memory loss, disorientation, incoherence, hallucinations, psychosis, delirium, hyperactivity, twitching or jerking movements, stereotypy, and seizures. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, particularly in the elderly and those with underlying organic brain disease, who tend to be more sensitive to the central anticholinergic effects of these drugs and in whom toxicity symptoms may be easily overlooked. Patients should be advised to notify their physician promptly if they experience potential symptoms of anticholinergic intoxication such as abdominal pain, fever, heat intolerance, blurred vision, confusion, and/or hallucinations. Ambulatory patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them. A reduction in anticholinergic dosages may be necessary if excessive adverse effects develop.

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MONITOR: Duloxetine is a moderate inhibitor of CYP450 2D6 and may increase the plasma concentrations of drugs that are substrates of the isoenzyme. According to the product labeling, when duloxetine (60 mg twice a day) was administered in conjunction with a single 50 mg dose of desipramine, a CYP450 2D6 substrate, the systemic exposure (AUC) of desipramine increased 3-fold. Conversely, many CYP450 2D6 substrates can also be competitive or noncompetitive inhibitors of the isoenzyme and may increase the plasma concentrations of duloxetine, which is partially metabolized by CYP450 2D6.

MANAGEMENT: Caution is advised if duloxetine must be used concomitantly with medications that undergo metabolism by CYP450 2D6, particularly those with a narrow therapeutic range such as tricyclic antidepressants, phenothiazines, beta blockers, and class IC antiarrhythmic agents (e.g., propafenone, flecainide). A lower initial dosage, as well as clinical and laboratory monitoring, may be appropriate for some drugs.

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MONITOR: Coadministration with inhibitors of CYP450 3A4 and/or 2D6 may increase the plasma concentrations of aripiprazole, which is primarily metabolized by these isoenzymes. According to the product labeling, administration of a single 15 mg dose of aripiprazole during treatment with the potent CYP450 3A4 inhibitor ketoconazole (200 mg/day for 14 days) increased the systemic exposure (AUC) to aripiprazole and its active metabolite, dehydro-aripiprazole, by 63% and 77%, respectively, compared to administration of aripiprazole alone. Likewise, administration of a 10 mg dose of aripiprazole with the potent CYP450 2D6 inhibitor quinidine (166 mg/day for 13 days) increased aripiprazole AUC by 112%, although dehydro-aripiprazole AUC was reduced by 35%.

MANAGEMENT: Pharmacologic response to aripiprazole should be monitored more closely whenever a CYP450 3A4 and/or 2D6 inhibitor is added to or withdrawn from therapy, and the aripiprazole dosage adjusted as necessary. The manufacturer recommends that aripiprazole dosage be reduced to one-half the normal dosage during concomitant administration with ketoconazole or quinidine, and additional dosage adjustments be made based on clinical evaluation. No dosage recommendations are available for concomitant administration with less potent CYP450 2D6 or 3A4 inhibitors.

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GENERALLY AVOID: Risperidone oral solution is not compatible with either tea or cola. In addition, alcohol may potentiate some of the pharmacologic effects of risperidone. Use in combination may result in additive central nervous system depression and/or impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Risperidone oral solution should not be mixed with tea or cola. It may be taken with water, coffee, orange juice, or lowfat milk. Patients should also be advised to avoid consumption of alcohol.

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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: Use of duloxetine in conjunction with chronic alcohol consumption may potentiate the risk of liver injury. Duloxetine alone can increase serum transaminase levels. In clinical trials, 0.3% of patients discontinued duloxetine due to liver transaminase elevations. The median time to detection was about two months. Three duloxetine-treated patients had liver injury as manifested by transaminase and bilirubin elevations, with evidence of obstruction. Substantial intercurrent ethanol use was present in each of these cases, which may have contributed to the abnormalities observed. Duloxetine does not appear to enhance the central nervous system effects of alcohol. When duloxetine and ethanol were administered several hours apart so that peak concentrations of each would coincide, duloxetine did not increase the impairment of mental and motor skills caused by alcohol.

MANAGEMENT: Due to the risk of liver injury, patients prescribed duloxetine should be counseled to avoid excessive use of alcohol. Duloxetine should generally not be prescribed to patients with substantial alcohol use.

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GENERALLY AVOID: Acute ethanol ingestion may potentiate the 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: Patients should be advised to avoid alcohol during benzodiazepine therapy.

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GENERALLY AVOID: Use of anticholinergic agents with alcohol may result in sufficient impairment of attention so as to render driving and operating machinery more hazardous. In addition, the potential for abuse may be increased with the combination. The mechanism of interaction is not established but may involve additive depressant effects on the central nervous system. No effect of oral propantheline or atropine on blood alcohol levels was observed in healthy volunteers when administered before ingestion of a standard ethanol load. However, one study found impairment of attention in subjects given atropine 0.5 mg or glycopyrrolate 1 mg in combination with alcohol.

MANAGEMENT: Alcohol should generally be avoided during therapy with anticholinergic agents. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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The recommended maximum number of medicines in the 'CNS drugs' category to be taken concurrently is usually three. Your list includes five medicines belonging to the 'CNS drugs' category:

• Risperdal (risperidone)
• Cymbalta (duloxetine)
• Abilify (aripiprazole)
• Klonopin (clonazepam)
• biperiden

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'psychotropic agents' category to be taken concurrently is usually three. Your list includes four medicines belonging to the 'psychotropic agents' category:

• Risperdal (risperidone)
• Cymbalta (duloxetine)
• Abilify (aripiprazole)
• Klonopin (clonazepam)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.

The recommended maximum number of medicines in the 'antipsychotics' category to be taken concurrently is usually one. Your list includes two medicines belonging to the 'antipsychotics' category:

• Risperdal (risperidone)
• Abilify (aripiprazole)

Note: In certain circumstances, the benefits of taking this combination of drugs may outweigh any risks. Always consult your healthcare provider before making changes to your medications or dosage.