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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MONITOR CLOSELY: The use of bupropion is associated with a dose-related risk of seizures. The risk may be further increased when coadministered with selective serotonin reuptake inhibitors (SSRI antidepressants or anorectics), monoamine oxidase inhibitors, neuroleptic agents, central nervous system stimulants, opioids, tricyclic antidepressants, other tricyclic compounds (e.g., cyclobenzaprine, phenothiazines), systemic steroids, or any substance that can reduce the seizure threshold (e.g., carbapenems, cholinergic agents, fluoroquinolones, interferons, chloroquine, mefloquine, lindane, theophylline). These agents are often individually epileptogenic and may have additive effects when combined. The estimated incidence of seizures is approximately 0.4% for immediate-release bupropion hydrochloride at dosages between 300 to 450 mg/day (equivalent to 348 to 522 mg/day of bupropion hydrobromide), but increases almost tenfold between 450 mg and 600 mg/day (equivalent to 522 and 696 mg/day of bupropion hydrobromide). Data for sustained-release (SR) bupropion hydrochloride revealed a seizure incidence of approximately 0.1% at dosages up to 300 mg/day and 0.4% at 400 mg/day. Likewise, in clinical trials, an overall seizure incidence of approximately 0.1% has been reported with extended-release (XL) bupropion hydrochloride at dosages up to 450 mg/day and approximately 0.39% at 450 mg/day. The 0.4% seizure incidence may exceed that of other marketed antidepressants by as much as 4-fold.

MANAGEMENT: Extreme caution is advised if bupropion is administered with any substance that can reduce the seizure threshold, particularly in the elderly and in patients with a history of seizures or other risk factors for seizures (e.g., head trauma; brain tumor; severe hepatic cirrhosis; metabolic disorders; CNS infections; excessive use of alcohol or sedatives; addiction to opiates, cocaine, or stimulants; diabetes treated with oral hypoglycemic agents or insulin). Bupropion as well as concomitant medications should be initiated at the lower end of the dosage range and titrated gradually as needed and as tolerated. The maximum recommended dosage for the specific bupropion formulation should not be exceeded. Bupropion should be discontinued and not restarted in patients who experience a seizure during treatment.

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MONITOR: Excessive use or abrupt discontinuation of benzodiazepines and other sedatives after chronic ingestion may precipitate seizures in patients receiving bupropion. Conversely, bupropion may antagonize the central pharmacologic effects of sedatives. Bupropion can cause agitation, anxiety, and insomnia and has been shown to decrease the sedative effect of diazepam in healthy volunteers given single doses of the drugs.

MANAGEMENT: Although sedatives may be prescribed to treat agitation, anxiety, and insomnia associated with bupropion use, patients should be alerted to the possibility of an increased risk of seizures during excessive exposure to these drugs. Patients should not attempt to alter the dosages or discontinue the medications on their own without consulting with their physician. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of sedatives.

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GENERALLY AVOID: Alcohol may potentiate the central nervous system (CNS) depressant effects of opioid analgesics including oxycodone. 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: Grapefruit juice may increase the plasma concentrations of oxycodone. The proposed mechanism is inhibition of CYP450 3A4-mediated metabolism of oxycodone by certain compounds present in grapefruit, resulting in decreased formation of metabolites noroxycodone and noroxymorphone and increased formation of oxymorphone due to a presumed shifting of oxycodone metabolism towards the CYP450 2D6-mediated route. In 12 healthy, nonsmoking volunteers, administration of a single 10 mg oral dose of oxycodone hydrochloride on day 4 of a grapefruit juice treatment phase (200 mL three times a day for 5 days) increased mean oxycodone peak plasma concentration (Cmax), systemic exposure (AUC) and half-life by 48%, 67% and 17% (from 3.5 to 4.1 hours), respectively, compared to administration during an equivalent water treatment phase. Grapefruit juice also decreased the metabolite-to-parent AUC ratio of noroxycodone by 44% and that of noroxymorphone by 45%. In addition, oxymorphone Cmax and AUC increased by 32% and 56%, but the metabolite-to-parent AUC ratio remained unchanged. Pharmacodynamic changes were modest and only self-reported performance was significantly impaired after grapefruit juice. Analgesic effects were not affected.

MANAGEMENT: Patients should not consume alcoholic beverages or use drug products that contain alcohol during treatment with oxycodone. Any history of alcohol or illicit drug use should be considered when prescribing oxycodone, and therapy initiated at a lower dosage if necessary. Patients should be closely monitored for signs and symptoms of sedation, respiratory depression, and hypotension. Due to a high degree of interpatient variability with respect to grapefruit juice interactions, patients treated with oxycodone may also want to avoid or limit the consumption of grapefruit and grapefruit juice.

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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: Excessive use or abrupt discontinuation of alcohol after chronic ingestion may precipitate seizures in patients receiving bupropion. Additionally, there have been rare postmarketing reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who drank alcohol during treatment with bupropion. According to one forensic report, a patient died after taking large doses of both bupropion and alcohol. It is uncertain whether a drug interaction was involved. Single-dose studies in healthy volunteers given bupropion and alcohol failed to demonstrate either a significant pharmacokinetic or pharmacodynamic interaction.

MANAGEMENT: The manufacturer recommends that alcohol consumption be minimized or avoided during bupropion treatment. The use of bupropion is contraindicated in patients undergoing abrupt discontinuation of alcohol.

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ADJUST DOSING INTERVAL: Consumption of certain foods as well as the timing of meals relative to dosing may affect the oral absorption of T4 thyroid hormone (i.e., levothyroxine). T4 oral absorption is increased by fasting and decreased by foods such as soybean flour (e.g., infant formula), cotton seed meal, walnuts, dietary fiber, calcium, and calcium fortified juices. Grapefruit or grapefruit products may delay the absorption of T4 thyroid hormone and reduce its bioavailability. The mechanism of this interaction is not fully understood.

MANAGEMENT: Some manufacturers recommend administering oral T4 as a single daily dose, on an empty stomach, one-half to one hour before breakfast. In general, oral preparations containing T4 thyroid hormone should be administered on a consistent schedule with regard to time of day and relation to meals to avoid large fluctuations in serum levels. Foods that may affect T4 absorption should be avoided within several hours of dosing if possible. Consult local guidelines for the administration of T4 in patients receiving enteral feeding.

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ADJUST DOSING INTERVAL: Concurrent administration of calcium-containing products may decrease the oral bioavailability of levothyroxine by one-third in some patients. Pharmacologic effects of levothyroxine may be reduced. The exact mechanism of interaction is unknown but may involve nonspecific adsorption of levothyroxine to calcium at acidic pH levels, resulting in an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, 20 patients with hypothyroidism who were taking a stable long-term regimen of levothyroxine demonstrated modest but significant decreases in mean free and total thyroxine (T4) levels as well as a corresponding increase in mean thyrotropin (thyroid-stimulating hormone, or TSH) level following the addition of calcium carbonate (1200 mg/day of elemental calcium) for 3 months. Four patients had serum TSH levels that were higher than the normal range. Both T4 and TSH levels returned to near-baseline 2 months after discontinuation of calcium, which further supported the likelihood of an interaction. In addition, there have been case reports suggesting decreased efficacy of levothyroxine during calcium coadministration. It is not known whether this interaction occurs with other thyroid hormone preparations.

MANAGEMENT: Some experts recommend separating the times of administration of levothyroxine and calcium-containing preparations by at least 4 hours. Monitoring of serum TSH levels is recommended. Patients with gastrointestinal or malabsorption disorders may be at a greater risk of developing clinical or subclinical hypothyroidism due to this interaction.

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MONITOR: Additive or synergistic effects on blood pressure may occur when bupropion is combined with sympathomimetic agents such as nasal decongestants, adrenergic bronchodilators, ophthalmic vasoconstrictors, and systemic vasopressors. Treatment with bupropion can result in elevated blood pressure and hypertension. In clinical practice, hypertension, in some cases severe and requiring acute treatment, has been observed in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have occurred in both patients with and without evidence of preexisting hypertension. Furthermore, postmarketing cases of hypertensive crisis have been reported during the initial titration phase with bupropion-naltrexone treatment.

MANAGEMENT: Caution is advised when bupropion is used with other drugs that increase dopaminergic or noradrenergic activity due to an increased risk of hypertension. Blood pressure and heart rate should be measured prior to initiating bupropion therapy and monitored at regular intervals consistent with usual clinical practice, particularly in patients with preexisting hypertension. Dose reduction or discontinuation of bupropion should be considered in patients who experience clinically significant and sustained increases in blood pressure or heart rate.

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MONITOR: The concomitant use of bupropion and nicotine replacement for smoking cessation may increase the risk of hypertension. In a clinical study (n=250), 6.1% of patients who used sustained-release bupropion with nicotine transdermal system developed treatment-emergent hypertension, compared to 2.5% of patients treated with bupropion alone, 1.6% treated with nicotine alone, and 3.1% treated with placebo. Three patients in the bupropion plus nicotine group and one patient in the nicotine-only group discontinued treatment due to hypertension. The majority had evidence of preexisting hypertension.

MANAGEMENT: Blood pressure monitoring is recommended for patients concomitantly using bupropion and nicotine replacement for smoking cessation.

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