Drug Interaction Report

CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In placebo-controlled trials in adults, oral ziprasidone increased the QTc interval by approximately 10 msec at the highest recommended daily dosage of 160 mg compared to placebo. In a study comparing the QT prolonging effect of several antipsychotic drugs at the maximum plasma concentration following administration alone in patient volunteers, the mean increase in QTc (QT interval corrected for heart rate) from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol, olanzapine, quetiapine, and risperidone), but was approximately 14 msec less than the prolongation observed for thioridazine. In another study evaluating the QT prolonging effect of intramuscular ziprasidone versus intramuscular haloperidol (control) at the maximum plasma concentration following administration in patient volunteers, the mean increase in QTc from baseline for ziprasidone (20 mg and 30 mg doses given 4 hours apart) was 4.6 msec after the first injection and 12.8 msec after the second injection, which at 30 mg is 1.5 times the highest recommended dose. The mean increase in QTc from baseline for haloperidol (7.5 mg and 10 mg doses given 4 hours apart) was 6.0 msec following the first injection and 14.7 msec following the second injection. No patients had a QTc interval exceeding 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of ziprasidone with other drugs that can prolong the QT interval is considered contraindicated.

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CONTRAINDICATED: Ziprasidone can cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In placebo-controlled trials in adults, oral ziprasidone increased the QTc interval by approximately 10 msec at the highest recommended daily dosage of 160 mg compared to placebo. In a study comparing the QT prolonging effect of several antipsychotic drugs at the maximum plasma concentration following administration alone in patient volunteers, the mean increase in QTc (QT interval corrected for heart rate) from baseline for ziprasidone ranged from approximately 9 to 14 msec greater than for four of the comparator drugs (haloperidol, olanzapine, quetiapine, and risperidone), but was approximately 14 msec less than the prolongation observed for thioridazine. In another study evaluating the QT prolonging effect of intramuscular ziprasidone versus intramuscular haloperidol (control) at the maximum plasma concentration following administration in patient volunteers, the mean increase in QTc from baseline for ziprasidone (20 mg and 30 mg doses given 4 hours apart) was 4.6 msec after the first injection and 12.8 msec after the second injection, which at 30 mg is 1.5 times the highest recommended dose. The mean increase in QTc from baseline for haloperidol (7.5 mg and 10 mg doses given 4 hours apart) was 6.0 msec following the first injection and 14.7 msec following the second injection. No patients had a QTc interval exceeding 500 msec. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of ziprasidone with other drugs that can prolong the QT interval is considered contraindicated.

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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: Omeprazole may increase the pharmacologic effects and serum levels of certain benzodiazepines via hepatic enzyme inhibition. Diazepam and triazolam are the only benzodiazepines that have been specifically studied in this regard.

MANAGEMENT: Patient should be observed for increased sedation. Reduced benzodiazepine dosage may be indicated, especially in the elderly. Benzodiazepines not metabolized via oxidation (i.e., lorazepam, oxazepam, temazepam) are not expected to interact and may be considered as alternatives.

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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: 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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GENERALLY AVOID: Asenapine may cause dose-related prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. The effects of asenapine on the QT/QTc interval were evaluated in a dedicated QT study using dosages of 5 mg, 10 mg, 15 mg, and 20 mg twice daily in 151 clinically stable patients with schizophrenia. At these dosages, asenapine was associated with increases in QTc interval ranging from 2 to 5 msec compared to placebo. No patient treated with asenapine experienced QTc increases >= 60 msec from baseline measurements or a QTc >= 500 msec. In short-term clinical trials using 5 mg or 10 mg twice daily dosages, post-baseline QT prolongations exceeding 500 msec were reported at comparable rates for asenapine and placebo. There were no reports of torsade de pointes arrhythmia or any other adverse reactions associated with delayed ventricular repolarization. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). The extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s). In addition, certain agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive parasympatholytic and central nervous system-depressant effects when used in combination with asenapine. Excessive parasympatholytic effects may include paralytic ileus, hyperthermia, mydriasis, blurred vision, tachycardia, urinary retention, psychosis, and seizures.

MANAGEMENT: Coadministration of asenapine with other drugs that can prolong the QT interval should generally be avoided. Caution and clinical monitoring are recommended if concomitant use is required. Patients should have regular ECGs and be monitored for arrhythmias when QT interval is prolonged. Persistent QTc measurements exceeding 500 msec will require suspension of asenapine therapy and immediate action to correct any concomitant risk factors before resuming treatment. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope. In addition, if combination therapy with agents with anticholinergic properties is required, caution is advised, particularly in the elderly and those with underlying organic brain disease. 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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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: Alcohol may potentiate the cardiovascular effects of amphetamines. The exact mechanism of interaction is unknown. In one study, concurrent administration of methamphetamine (30 mg intravenously) and ethanol (1 gm/kg orally over 30 minutes) increased heart rate by 24 beats/minute compared to methamphetamine alone. This increases cardiac work and myocardial oxygen consumption, which may lead to more adverse cardiovascular effects than either agent alone. Subjective effects of ethanol were diminished in the eight study subjects, but those of methamphetamine were not affected. The pharmacokinetics of methamphetamine were also unaffected except for a decrease in the apparent volume of distribution at steady state. The interaction was suspected in a case report of a 20-year-old male who experienced retrosternal chest pain shortly after drinking alcohol and taking a double dose of his amphetamine/dextroamphetamine medication (Adderall 15 mg X 2) to stay alert. The patient had no family history of cardiovascular diseases, and his past medical history was remarkable only for ADHD. Prior to the episode, the patient had not taken his medication for weeks and had been drinking whiskey the previous three nights before going to bed. The patient was diagnosed with myocardial infarction likely secondary to amphetamine-induced coronary vasospasm.

MANAGEMENT: Concomitant use of amphetamines and alcohol should be avoided if possible, especially in patients with a history of heart disease.

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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 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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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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The recommended maximum number of medicines in the 'Central Nervous System (CNS) Drugs' category to be taken concurrently is usually three. Your list includes six medicines belonging to the 'Central Nervous System (CNS) Drugs' category:

• gabapentin
• Cogentin (benztropine)
• Geodon (ziprasidone)
• Klonopin (clonazepam)
• Saphris (asenapine)
• Vyvanse (lisdexamfetamine)

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:

• Geodon (ziprasidone)
• Saphris (asenapine)

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.