Drug Interaction Report

GENERALLY AVOID: Anagrelide can cause dose-dependent prolongation of the QT interval. Theoretically, coadministration with other agents that can prolong the QT interval may result in additive effects and increased risk of ventricular arrhythmias including torsade de pointes and sudden death. In 60 healthy adult volunteers given single doses of anagrelide, the maximum mean change in QTcI (individual subject correction) from placebo after baseline correction was 7.0 msec after a 0.5 mg dose and 13.0 msec after a 2.5 mg dose. Torsade de pointes and ventricular tachycardia have been reported with anagrelide treatment. In general, the risk of an individual agent or a combination of agents causing ventricular arrhythmia in association with QT prolongation is largely unpredictable but may be increased by certain underlying risk factors such as congenital long QT syndrome, cardiac disease, and electrolyte disturbances (e.g., hypokalemia, hypomagnesemia). In addition, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

MANAGEMENT: Coadministration of anagrelide with other drugs that can prolong the QT interval should generally be avoided. Patients receiving anagrelide should have a cardiovascular examination, including an ECG, prior to initiation of treatment and monitored for cardiovascular effects during treatment. Hypokalemia or hypomagnesemia must be corrected prior to therapy and electrolytes monitored periodically during therapy. Anagrelide should not be used in the presence of known risk factors for QT interval prolongation such as congenital long QT syndrome or a history of acquired QTc prolongation. Periodic electrocardiograms are recommended in patients with heart failure, bradyarrhythmias, or electrolyte abnormalities. Patients should be advised to seek prompt medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, lightheadedness, fainting, palpitation, irregular heart rhythm, shortness of breath, or syncope.

MONITOR: Anagrelide and aspirin may potentiate each other's antiplatelet effects when they are coadministered. In two clinical studies with healthy subjects, the administration of single-dose anagrelide 1 mg and aspirin 900 mg or repeat dose once-daily anagrelide 1 mg with aspirin 75 mg resulted in greater antiplatelet aggregation effects than administration of aspirin alone. There were no effects on bleeding time, prothrombin time (PT), or activated partial thromboplastin time (aPTT) with the single-dose aspirin and anagrelide regimen. Major hemorrhages have been reported in some patients with essential thrombocythemia who received both aspirin and anagrelide.

MANAGEMENT: Before initiation of combination treatment, the risks and benefits should be assessed, especially in patients who have a high risk for hemorrhage and/or whose platelet counts are greater than 1000 x 10(9)/L.

MONITOR: Theoretically, coadministration with anagrelide may increase the plasma concentrations and the risk of toxicity of drugs that are substrates of CYP450 1A2. The proposed mechanism, based on in vitro data, is decreased clearance due to anagrelide-mediated inhibition of CYP450 1A2 metabolism.

MANAGEMENT: Until more information is available, caution is advised if anagrelide is used concomitantly with drugs that are substrates of CYP450 1A2, particularly those with a narrow therapeutic range. Dosage adjustments as well as clinical and laboratory monitoring may be appropriate for some drugs whenever anagrelide is added to or withdrawn from therapy. Patients should be monitored for the development of adverse effects.

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.

GENERALLY AVOID: Alcohol may have additive CNS- and/or respiratory-depressant effects with propoxyphene. Misuse of propoxyphene, either alone or in combination with other CNS depressants, has been a major cause of drug-related deaths, particularly in patients with a history of emotional disturbances, suicidal ideation, or alcohol and drug abuse.

MANAGEMENT: The use of alcohol during propoxyphene therapy should be avoided. Patients should be warned not to exceed the recommended dosage of propoxyphene and to avoid activities requiring mental alertness until they know how these agents affect them.

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.

The effect of grapefruit juice on the pharmacologic activity of caffeine is controversial. One report suggests that grapefruit juice increases the effect of caffeine. The proposed mechanism is inhibition of cytochrome P-450 metabolism of caffeine. However, a well-conducted pharmacokinetic/pharmacodynamic study did not demonstrate this effect. The clinical significance of this potential interaction is unknown.

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.