Drug Interactions between Adalat and Docefrez

GENERALLY AVOID: Coadministration with inhibitors of CYP450 3A4, such as grapefruit juice, may significantly increase the plasma concentrations of docetaxel, which is a substrate of the isoenzyme. Current data suggest that consumption of large quantities of grapefruit juice inhibit both intestinal and hepatic CYP450 3A4 due to certain compounds present in grapefruit. In a pharmacokinetic study consisting of 7 cancer patients, mean dose-normalized docetaxel systemic exposure (AUC) increased by 2.2-fold and clearance decreased by 49% when intravenous docetaxel was given at a reduced dosage of 10 mg/m2 in combination with the potent CYP450 3A4 inhibitor ketoconazole (200 mg orally once daily for 3 days) compared to docetaxel administered alone at 100 mg/m2. In addition, a case report of a 52-year-old woman with esophageal squamous cell carcinoma receiving a twice weekly chemotherapy regimen including intravenous docetaxel (40 mg/m2) reported that docetaxel AUC increased by 65% compared with the AUC target of 1.96 mg*h/L and clearance decreased by 63%, with a 71% reduction in the patient's neutrophil count. In the absence of other CYP450 3A4 inhibitors, these effects were attributed to daily consumption of 250 mL of grapefruit juice, which the patient had been consuming for at least 3 months. Two weeks after the patient ceased the grapefruit juice, the docetaxel AUC was closer to the target value and the neutrophil count reduction was less than 35%.

MANAGEMENT: The use of docetaxel in combination with grapefruit and grapefruit juice should generally be avoided. If concomitant use is required, a reduced dosage of docetaxel should be considered, particularly if used with large amounts of grapefruit juice, and therapeutic drug monitoring of docetaxel considered per local treatment protocols. Patients should be closely monitored for the development of docetaxel toxicity such as myelosuppression, stomatitis, neurotoxicity (e.g., paraesthesia, dysesthesia, pain), myalgia, asthenia, fluid retention, nausea, vomiting, and diarrhea.

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GENERALLY AVOID: The consumption of grapefruit juice may be associated with significantly increased plasma concentrations of some calcium channel blockers (CCBs) when they are administered orally. The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit. The interaction has been reported with the dihydropyridine CCBs (in roughly decreasing order of magnitude) felodipine, nisoldipine, nifedipine, and nimodipine, often with a high degree of interindividual variability. Grapefruit juice caused more than twofold increases in felodipine, nifedipine, and nisoldipine AUCs.

MANAGEMENT: The manufacturers of nifedipine and nisoldipine recommend avoiding grapefruit juice. Patients treated orally with other calcium channel blockers should be advised to avoid consumption of large amounts of grapefruits and grapefruit juice to prevent any undue fluctuations in serum drug levels. Increased effects on blood pressure may persist for up to 4 days after the consumption of grapefruit juice. Monitoring for calcium channel blocker adverse effects (e.g., headache, hypotension, syncope, tachycardia, edema) is recommended.

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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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MONITOR: Calcium-containing products may decrease the effectiveness of calcium channel blockers by saturating calcium channels with calcium. Calcium chloride has been used to manage acute severe verapamil toxicity.

MANAGEMENT: Management consists of monitoring the effectiveness of calcium channel blocker therapy during coadministration with calcium products.

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