Drug Interactions between Donnatal Extentabs and tamoxifen

GENERALLY AVOID: Coadministration with potent inducers of CYP450 3A4 may significantly decrease the plasma concentrations of tamoxifen and its active metabolites. According to the product labeling, tamoxifen is primarily metabolized by CYP450 3A4 to N-desmethyltamoxifen, an antiestrogenic metabolite with similar biological activity to tamoxifen but an elimination half-life that is estimated to be approximately 10 to 14 days versus 5 to 7 days for tamoxifen. N-desmethyltamoxifen itself is further metabolized by CYP450 2D6 and possibly other CYP450 enzymes to endoxifen, a major metabolite that is thought to be primarily responsible for tamoxifen's therapeutic effect. When a single 80 mg oral dose of tamoxifen was administered to 10 healthy volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin at a dosage of 600 mg once daily for 5 days, tamoxifen peak plasma concentration (Cmax), systemic exposure (AUC) and elimination half-life decreased by 55%, 86% and 44%, respectively, compared to pretreatment with placebo. In addition, rifampin decreased the AUC and half-life of N-desmethyltamoxifen by 62% and 36%, respectively, and increased the Cmax by approximately 50% compared to placebo. These results indicate that rifampin enhanced the metabolism of tamoxifen during both the presystemic and elimination phases. Similar changes in the AUCs of tamoxifen (81% to 86% reductions) and N-desmethyltamoxifen (62% to 74% reductions) were observed in an interim safety analysis of four breast cancer patients receiving tamoxifen 20 mg or 40 mg once daily who participated in a pharmacokinetic study on the induction effects of rifampin 600 mg given daily for 15 days. In these four patients, the AUCs of endoxifen were also significantly reduced by 28% to 85% following coadministration with rifampin, which led to cessation of further patient enrollment into the trial. In another study, patients with glioma who received high-dose tamoxifen with phenytoin (n=15) demonstrated a 60% lower mean plasma tamoxifen concentration than patients not on concomitant phenytoin (n=10), although the difference did not reach statistical significance due to high interpatient variability and low patient numbers. The interaction has also been described in case reports of two tamoxifen-treated patients who had significantly reduced and subtherapeutic endoxifen levels during or after coadministration with a potent CYP450 inducer. One of them was receiving phenytoin and the other, rifampin. Induction of endoxifen clearance via P-glycoprotein-mediated efflux and/or uridine diphosphate glucuronosyltransferase (UGT)-mediated metabolism may be involved. The extent to which other potent CYP450 3A4 inducers may affect tamoxifen and its active metabolites is unknown.

MANAGEMENT: Until more information is available, concomitant use of tamoxifen with potent CYP450 3A4 inducers should be avoided when possible, particularly if they are to be administered for a prolonged period. Otherwise, therapeutic drug monitoring of tamoxifen and endoxifen is recommended to optimize therapy.

MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of 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. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, 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. 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.

MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of 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. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, 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. 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.

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.

MONITOR: Agents with anticholinergic properties (e.g., sedating antihistamines; antispasmodics; neuroleptics; phenothiazines; skeletal muscle relaxants; tricyclic antidepressants; disopyramide) may have additive effects when used in combination. Excessive parasympatholytic effects may result in paralytic ileus, hyperthermia, heat stroke, and the anticholinergic intoxication syndrome. Peripheral symptoms of 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. Central nervous system-depressant effects may also be additively or synergistically increased when these agents are combined, especially in elderly or debilitated patients. Use of neuroleptics in combination with other neuroleptics or anticholinergic agents may increase the risk of tardive dyskinesia. In addition, some neuroleptics and tricyclic antidepressants may cause prolongation of the QT interval and theoretically, concurrent use of two or more drugs that can cause QT interval prolongation may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death.

MANAGEMENT: Caution is advised when agents with anticholinergic properties are combined, 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. 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.