Drug Interactions between Byvalson and Pyrelle HB

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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MONITOR: Coadministration with barbiturates may decrease the plasma concentrations and pharmacologic effects of certain beta-blockers when administered orally. The proposed mechanism is barbiturate induction of hepatic microsomal and first-pass metabolism. The interaction has been studied with alprenolol, metoprolol and timolol, but probably can occur with any beta-blocker that is primarily metabolized in the liver such as propranolol. In six healthy volunteers, pretreatment with pentobarbital (100 mg daily for 10 days) reduced the plasma levels of alprenolol (200 mg single oral dose) and its metabolite 4-hydroxyalprenolol by approximately 40% without altering their plasma half-lives. The inhibition of exercise-induced tachycardia during a 7-hour period following alprenolol administration was reduced from 14% to 10.7% by pentobarbital, and the reduction was proportional to the decreased drug levels. In another study, pentobarbital reduced alprenolol levels by 59% and 4-hydroxyalprenolol levels by 24% in 6 hypertensive patients treated with alprenolol 400 mg twice daily. The effect of pentobarbital was significant after 3 doses and declined over 4 to 5 days after discontinuation. The decreases were associated with a 6% increase in pulse rate and 8% increase in systolic and 9% increase in diastolic blood pressure, as well as an 18% reduction in inhibition of exercise tachycardia by alprenolol. In eight healthy subjects, administration of metoprolol (100 mg single oral dose) with pentobarbital (100 mg daily for 10 days) resulted in a mean 32% reduction in metoprolol systemic exposure (AUC) compared to administration alone. The same dose of pentobarbital given for 7 days reduced AUC of timolol (10 mg) by just 24% in 12 healthy volunteers.

MANAGEMENT: Barbiturates may variously reduce the effects of certain beta-blockers when given for more than a few days. Pharmacologic response to beta-blockers should be monitored more closely whenever a barbiturate is added to or withdrawn from therapy, and the beta-blocker dosage adjusted as necessary. Renally excreted beta-blockers such as atenolol, carteolol, nadolol, or sotalol are not expected to interact.

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MONITOR: Anticholinergic agents frequently cause drowsiness and other central nervous system-depressant effects that may be additive with those induced by beta blockers. In addition, these agents may increase heart rate and theoretically may counteract the bradycardic effects of beta blockers. Pharmacokinetically, anticholinergic agents may delay the gastrointestinal absorption of beta blockers and other drugs that are administered orally. The proposed mechanism involves increased gastrointestinal transit time due to reduction of stomach and intestinal motility by anticholinergic agents. In healthy volunteers, pretreatment with propantheline has been shown to prolong the time to reach peak plasma concentration (Tmax) for both atenolol and metoprolol. Propantheline also decreased metoprolol peak plasma concentration (Cmax) but had no effect on its systemic exposure (AUC). In contrast, propantheline increased atenolol AUC but had no effect on its Cmax. The clinical relevance of these changes is probably minimal.

MANAGEMENT: Clinicians should be aware of the potential for diminished effects of beta blockers during coadministration with anticholinergic agents. Patients should also be monitored for potentially excessive CNS adverse effects (e.g., drowsiness, dizziness, lightheadedness, confusion, blurred vision) if these agents are used in combination. Patients should be counseled to avoid activities requiring mental alertness until they know how these agents affect them.

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GENERALLY AVOID: In the Valsartan Heart Failure Trial, the combination of valsartan with a beta-blocker and an ACE inhibitor was associated with unfavorable outcomes on morbidity and mortality in heart failure patients. The mechanism is unknown.

MANAGEMENT: The manufacturer recommends that the triple combination of valsartan with a beta-blocker and an ACE inhibitor be avoided in heart failure patients.

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