Drug Interactions between hydrochlorothiazide / methyldopa and Percodan

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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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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GENERALLY AVOID: The concurrent use of aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) and ethanol may lead to gastrointestinal (GI) blood loss. The mechanism may be due to a combined local effect as well as inhibition of prostaglandins leading to decreased integrity of the GI lining.

MANAGEMENT: Patients should be counseled on this potential interaction and advised to refrain from alcohol consumption while taking aspirin or NSAIDs.

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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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ADJUST DOSING INTERVAL: The oral bioavailability and pharmacologic effects of methyldopa may be decreased during concurrent administration with iron-containing products. The proposed mechanism is chelation of methyldopa by the iron cation, forming an insoluble complex that is poorly absorbed from the gastrointestinal tract. In one study, five hypertensive patients receiving chronic methyldopa therapy (250 mg to 1500 mg daily) all had elevated blood pressure following the addition of ferrous sulfate 325 mg three times daily for 2 weeks. The systolic pressure had increased by more than 15 mmHg in three of the patients and the diastolic pressure increased by more than 10 mmHg in two. Blood pressure returned to baseline within 7 days of discontinuing the iron. In 12 normal subjects, administration of methyldopa 500 mg with ferrous sulfate 325 mg or ferrous gluconate 600 mg resulted in an 88% and 79% reduction, respectively, in the renal excretion of unmetabolized, free methyldopa compared to administration of methyldopa alone. In another study, administration of ferrous sulfate simultaneously with methyldopa reduced the bioavailability of methyldopa by 83%, while administration one hour or two hours before methyldopa reduced its bioavailability by 55% and 42%, respectively.

MANAGEMENT: Until more information is available, patients receiving methyldopa in combination with iron-containing products should be advised to separate the times of administration by as much as possible. Patients should be monitored closely for altered hypertensive effect and methyldopa dosage increased as necessary. Selection of an alternative antihypertensive therapy may be necessary.

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One study has reported that coadministration of caffeine and aspirin lead to a 25% increase in the rate of appearance and 17% increase in maximum concentration of salicylate in the plasma. A significantly higher area under the plasma concentration time curve of salicylate was also reported when both drugs were administered together. The exact mechanism of this interaction has not been specified. Physicians and patients should be aware that coadministration of aspirin and caffeine may lead to higher salicylate levels faster.

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