Drug Interactions between Dolgic LQ and imatinib

MONITOR: Barbiturates may increase the hepatotoxic potential of acetaminophen and decrease its therapeutic effects. The mechanism may be related to accelerated CYP450 metabolism of acetaminophen with consequent increase in hepatotoxic metabolites. This interaction is of greatest concern in cases of acetaminophen overdose.

MANAGEMENT: Monitoring for altered efficacy and safety is recommended. Prolonged use or high doses of acetaminophen should be avoided by patients on barbiturate therapy.

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MONITOR: In vitro inhibition data suggest that coadministration with imatinib may increase the plasma concentrations of acetaminophen. The proposed mechanism is imatinib inhibition of acetaminophen clearance via O-glucuronidation. However, no specific pharmacokinetic studies in humans have been performed. Pharmacodynamically, the potential may exist for additive adverse effects on the liver, since both agents individually are associated with hepatotoxicity. Cases of liver injury, including hepatic failure and hepatic necrosis, have been observed with imatinib use, particularly when combined with high-dose chemotherapy regimens. Most cases have been reversible, although approximately 0.5% have required permanent discontinuation of imatinib. In a phase 2 clinical trial, a patient who received a bone marrow transplant and had been taking acetaminophen (3000 to 3500 mg/day) regularly for fever died of acute liver failure 12 days after starting treatment with imatinib 600 mg/day. In a postmarketing case report, a patient developed severe hepatitis associated with coagulopathy five months after starting imatinib 400 mg/day for chronic myeloid leukemia. She began taking acetaminophen 500 to 1000 mg/day after the onset of symptoms. During hospitalization, her condition progressed to encephalopathy and she subsequently died of a cardiac arrest. Whether acetaminophen affected the clinical course and outcome of her hepatitis cannot be determined.

MANAGEMENT: Caution is advised if imatinib is used in combination with acetaminophen, particularly at higher dosages of the latter. All patients treated with imatinib should have liver function tests (transaminases, bilirubin, and alkaline phosphatase) prior to initiation of therapy and monthly thereafter or as clinically indicated. If elevations in bilirubin greater than 3 times institutional upper limit of normal (IULN) or liver transaminases greater than 5 times IULN occur, imatinib should be withheld until bilirubin levels decline to less than 1.5 times IULN and transaminase levels to less than 2.5 times IULN. Treatment may then be resumed at a reduced daily dosage (e.g., in adults: 400 mg to 300 mg, 600 mg to 400 mg, or 800 mg to 600 mg; in children: 340 to 260 mg/m2/day or 260 mg/m2/day to 200 mg/m2/day). Patients should be advised to seek medical attention if they experience potential signs and symptoms of hepatotoxicity such as fever, rash, anorexia, nausea, vomiting, fatigue, right upper quadrant pain, dark urine, and jaundice. In addition, they should not take over-the-counter medications such as analgesics containing acetaminophen, flu preparations, or herbal products without first talking to their healthcare provider.

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MONITOR: Coadministration with inducers of CYP450 3A4 may decrease the plasma concentrations of imatinib, which is primarily metabolized by the isoenzyme. When a single 400 mg oral dose of imatinib was administered to 14 healthy adult volunteers following pretreatment with the potent CYP450 3A4 inducer rifampin (600 mg once daily for 8 days), mean imatinib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by 54% and 74%, respectively, compared to administration alone. The oral clearance of imatinib was increased by 3.8-fold during rifampin coadministration. Similar results were observed in patients with malignant gliomas receiving imatinib 400 to 1200 mg/day concomitantly with enzyme-inducing antiepileptic drugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and primidone. The mean dose-normalized AUC for imatinib decreased by 73% compared to patients not on EIAEDs. In two published studies, concomitant administration of imatinib and a product containing St. John's wort led to a 30% to 32% reduction in the AUC of imatinib. The extent to which other, less potent CYP450 3A4 inducers may interact with imatinib is unknown.

MANAGEMENT: The potential for diminished pharmacologic effects of imatinib should be considered during coadministration with CYP450 3A4 inducers. Alternative treatments may be required if an interaction is suspected.

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