Drug Interaction Report

GENERALLY AVOID: Concomitant use of opioids with benzodiazepines or other central nervous system (CNS) depressants (e.g., nonbenzodiazepine sedatives/hypnotics, anxiolytics, muscle relaxants, general anesthetics, antipsychotics, other opioids, alcohol) may result in profound sedation, respiratory depression, coma, and death. The risk of hypotension may also be increased with some CNS depressants (e.g., alcohol, benzodiazepines, phenothiazines).

MANAGEMENT: The use of opioids in conjunction with benzodiazepines or other CNS depressants should generally be avoided unless alternative treatment options are inadequate. If coadministration is necessary, the dosage and duration of each drug should be limited to the minimum required to achieve desired clinical effect, with cautious titration and dosage adjustments when needed. Patients should be monitored closely for signs and symptoms of respiratory depression and sedation, and advised to avoid driving or operating hazardous machinery until they know how these medications affect them. Cough medications containing opioids (e.g., codeine, hydrocodone) should not be prescribed to patients using benzodiazepines or other CNS depressants including alcohol. For patients who have been receiving extended therapy with both an opioid and a benzodiazepine and require discontinuation of either medication, a gradual tapering of dose is advised, since abrupt withdrawal may lead to withdrawal symptoms. Severe cases of benzodiazepine withdrawal, primarily in patients who have received excessive doses over a prolonged period, may result in numbness and tingling of extremities, hypersensitivity to light and noise, hallucinations, and epileptic seizures.

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GENERALLY AVOID: Several case reports suggest that serotonin reuptake inhibitors may potentiate the pharmacologic response to sympathomimetic agents. The exact mechanism of interaction is unclear. In one case report, a patient experienced jitteriness, racing thoughts, stomach cramps, dry eyes, palpitations, tremors, and restlessness following a single dose of phentermine ingested approximately a week after she had discontinued fluoxetine. Because of the long half-life of fluoxetine and its metabolite, an interaction with fluoxetine is possible. Similar toxic reactions have been reported when fluoxetine was used concomitantly with amphetamine or phenylpropanolamine. Additionally, some sympathomimetic agents such as amphetamines may possess serotonergic activity and should generally not be administered with serotonin reuptake inhibitors because of the additive risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. The interaction was suspected in a patient treated with dexamphetamine who developed symptoms consistent with the serotonin syndrome approximately 2 weeks after the addition of venlafaxine. The medications were discontinued and the patient was given cyproheptadine for suspected serotonin syndrome, whereupon symptoms promptly resolved. A second episode occurred when dexamphetamine was subsequently resumed and citalopram added. The patient improved following cessation of citalopram on his own, and residual symptoms were successfully treated with cyproheptadine.

MANAGEMENT: In general, amphetamines and other sympathomimetic appetite suppressants should not be combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Close monitoring for enhanced sympathomimetic effects and possible serotonin syndrome is recommended if these agents must be used together. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

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GENERALLY AVOID: Several case reports suggest that serotonin reuptake inhibitors may potentiate the pharmacologic response to sympathomimetic agents. The exact mechanism of interaction is unclear. In one case report, a patient experienced jitteriness, racing thoughts, stomach cramps, dry eyes, palpitations, tremors, and restlessness following a single dose of phentermine ingested approximately a week after she had discontinued fluoxetine. Because of the long half-life of fluoxetine and its metabolite, an interaction with fluoxetine is possible. Similar toxic reactions have been reported when fluoxetine was used concomitantly with amphetamine or phenylpropanolamine. Additionally, some sympathomimetic agents such as amphetamines may possess serotonergic activity and should generally not be administered with serotonin reuptake inhibitors because of the additive risk of serotonin syndrome, which is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. The interaction was suspected in a patient treated with dexamphetamine who developed symptoms consistent with the serotonin syndrome approximately 2 weeks after the addition of venlafaxine. The medications were discontinued and the patient was given cyproheptadine for suspected serotonin syndrome, whereupon symptoms promptly resolved. A second episode occurred when dexamphetamine was subsequently resumed and citalopram added. The patient improved following cessation of citalopram on his own, and residual symptoms were successfully treated with cyproheptadine.

MANAGEMENT: In general, amphetamines and other sympathomimetic appetite suppressants should not be combined with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). Close monitoring for enhanced sympathomimetic effects and possible serotonin syndrome is recommended if these agents must be used together. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea.

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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: Opioids may potentiate the effects of serotonergic agents and increase the risk of serotonin syndrome. The interaction has primarily been reported with the phenylpiperidine opioids (e.g., meperidine, fentanyl) and tramadol, which are known to possess some serotonergic activity, although a few cases have involved other opioids such as oxycodone, methadone, morphine, hydromorphone, codeine, and buprenorphine. Serotonin syndrome is a rare but serious and potentially fatal condition thought to result from hyperstimulation of brainstem 5-HT1A and 2A receptors. Symptoms of the serotonin syndrome may include mental status changes such as irritability, altered consciousness, confusion, hallucinations, and coma; autonomic dysfunction such as tachycardia, hyperthermia, diaphoresis, shivering, blood pressure lability, and mydriasis; neuromuscular abnormalities such as hyperreflexia, myoclonus, tremor, rigidity, and ataxia; and gastrointestinal symptoms such as abdominal cramping, nausea, vomiting, and diarrhea. Since many serotonergic agents can also cause central nervous system depression, concomitant use with opioids may result in increased sedation and impairment of judgment, thinking, and psychomotor skills.

MANAGEMENT: Caution is advised when opioids are used concomitantly with serotonergic agents such as selective serotonin reuptake inhibitors (SSRIs), serotonin and norepinephrine reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), tricyclic antidepressants (TCAs), other antidepressants/psychotropic agents (e.g., amoxapine, buspirone, lithium, maprotiline, mirtazepine, nefazodone, trazodone, vilazodone), 5-HT1 receptor agonists (triptans), 5-HT3 receptor antagonists, cyclobenzaprine, dextromethorphan, 5-hydroxytryptophan, and St. John's wort. Patients should be monitored for symptoms of the serotonin syndrome during treatment. Particular caution is advised when increasing the dosages of these agents. If serotonin syndrome develops or is suspected during the course of therapy, all serotonergic agents should be discontinued immediately and supportive care rendered as necessary. Moderately ill patients may also benefit from the administration of a serotonin antagonist (e.g., cyproheptadine, chlorpromazine). Severe cases should be managed under consultation with a toxicologist and may require sedation, neuromuscular paralysis, intubation, and mechanical ventilation in addition to the other measures. Patients should also be advised of potentially additive central nervous system effects from these agents and to avoid hazardous activities requiring complete mental alertness and motor coordination until they know how these agents affect them.

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GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including hydrocodone. Concomitant use may result in additive CNS depression and impairment of judgment, thinking, and psychomotor skills. In more severe cases, hypotension, respiratory depression, profound sedation, coma, or even death may occur.

GENERALLY AVOID: Consumption of alcohol while taking some sustained-release formulations of hydrocodone may cause rapid release of the drug, resulting in high systemic levels of hydrocodone that may be potentially lethal. Alcohol apparently can disrupt the release mechanism of some sustained-release formulations. In study subjects, the rate of absorption of hydrocodone from an extended-release formulation was found to be affected by coadministration with 40% alcohol in the fasted state, as demonstrated by an average 2.4-fold (up to 3.9-fold in one subject) increase in hydrocodone peak plasma concentration and a decrease in the time to peak concentration. Alcohol also increased the extent of absorption by an average of 1.2-fold (up to 1.7-fold in one subject).

GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of hydrocodone. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of hydrocodone by certain compounds present in grapefruit. Increased hydrocodone concentrations could conceivably increase or prolong adverse drug effects and may cause potentially fatal respiratory depression.

MANAGEMENT: Patients taking sustained-release formulations of hydrocodone should not consume alcohol or use medications that contain alcohol. In general, potent narcotics such as hydrocodone should not be combined with alcohol. Patients should also avoid consumption of grapefruit or grapefruit juice during treatment with hydrocodone.

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GENERALLY AVOID: Chronic, excessive consumption of alcohol may increase the risk of acetaminophen-induced hepatotoxicity, which has included rare cases of fatal hepatitis and frank hepatic failure requiring liver transplantation. The proposed mechanism is induction of hepatic microsomal enzymes during chronic alcohol use, which may result in accelerated metabolism of acetaminophen and increased production of potentially hepatotoxic metabolites.

MANAGEMENT: In general, chronic alcoholics should avoid regular or excessive use of acetaminophen. Alternative analgesic/antipyretic therapy may be appropriate in patients who consume three or more alcoholic drinks per day. However, if acetaminophen is used, these patients should be cautioned not to exceed the recommended dosage (maximum 4 g/day in adults and children 12 years of age or older).

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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 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 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: 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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