Drug Interactions between amoxicillin / clarithromycin / lansoprazole and panobinostat

GENERALLY AVOID: Panobinostat 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 a premarketing multiple myeloma trial, QTc prolongation with values between 451 to 480 msec and between 481 to 500 msec occurred in 10.8% and 1.3% of patients receiving panobinostat, respectively. A maximum QTcF increase from baseline of 31 to 60 msec and greater than 60 msec was observed in 14.5% and 0.8% of panobinostat-treated patients, respectively. No episodes of QTcF prolongation exceeding 500 msec were reported with panobinostat given at a dose of 20 mg in combination with bortezomib and dexamethasone in the multiple myeloma trial. Pooled clinical data from over 500 patients treated with panobinostat monotherapy at different dose levels for various indications have shown that the incidence of CTC Grade 3 QTc prolongation (i.e., QTcF >500 msec) was approximately 1% overall and 5% or more at a dose of 60 mg or higher. 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, hypocalcemia). Moreover, the extent of drug-induced QT prolongation is dependent on the particular drug(s) involved and dosage(s) of the drug(s).

ADJUST DOSE: Coadministration with potent inhibitors of CYP450 3A4 may increase the plasma concentrations of panobinostat, which is partially metabolized by the isoenzyme. In 14 patients with advanced or metastatic solid tumors, administration of a single 20 mg dose of panobinostat on day 4 of multiple once daily dosing of 400 mg ketoconazole, a potent CYP450 3A4 inhibitor, resulted in 1.6- and 1.8-fold increases in mean panobinostat peak plasma concentration (Cmax) and systemic exposure (AUC), respectively, compared to administration of panobinostat alone. Ketoconazole caused a greater than 2-fold increase in Cmax and AUC of panobinostat in a limited number of patients. QTc prolongation >30 ms over baseline occurred in 5 patients during concomitant administration, compared to 4 patients during panobinostat alone and 3 patients during ketoconazole alone. Other ECG abnormalities occurred in 6 patients during concomitant administration and 3 patients during either panobinostat or ketoconazole alone. No significant alteration in time to maximum concentration (Tmax) or half-life of panobinostat was observed.

MANAGEMENT: Concomitant use of panobinostat with potent CYP450 3A4 inhibitors that can also prolong the QT interval including ceritinib, clarithromycin, ketoconazole, posaconazole, saquinavir, telithromycin, and voriconazole should generally be avoided. If coadministration with these agents is required, the manufacturer recommends reducing the dose of panobinostat to 10 mg for the treatment of multiple myeloma, given in combination with bortezomib and dexamethasone. ECG and serum electrolytes, including potassium, magnesium and calcium, should be monitored before starting panobinostat therapy and periodically during treatment as clinically indicated. In the premarketing trial, ECGs were performed at baseline and prior to initiation of each cycle for the first 8 cycles. Panobinostat should not be started if baseline QTc is greater than 450 msec. Likewise, treatment should be interrupted in patients who develop QTc prolongation of 480 msec or greater until recovery to less than or equal to Grade 1, then resumed at a reduced dose. In case of recurrence, therapy should be withheld until recovery to less than or equal to Grade 1, then resumed at a further reduced dose if necessary. Permanently discontinue panobinostat therapy if Grade 3 or 4 QTc prolongation does not resolve. 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.

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MONITOR: Coadministration with clarithromycin may increase the plasma concentrations of lansoprazole. The proposed mechanism is clarithromycin inhibition of intestinal (first-pass) and hepatic metabolism of lansoprazole via CYP450 3A4. Although lansoprazole is primarily metabolized by CYP450 2C19 in the liver, 3A4-mediated metabolism is the predominant pathway in individuals who are 2C19-deficient (approximately 3% to 5% of the Caucasian and 17% to 20% of the Asian population). Additionally, inhibition of P-glycoprotein intestinal efflux transporter by clarithromycin may also contribute to the interaction, resulting in increased bioavailability of lansoprazole. In 18 healthy volunteers--six each of homozygous extensive metabolizers (EMs), heterozygous EMs, and poor metabolizers (PMs) of CYP450 2C19--clarithromycin (400 mg orally twice a day for 6 days) increased the peak plasma concentration (Cmax) of a single 60 mg oral dose of lansoprazole by 1.47, 1.71- and 1.52-fold, respectively, and area under the concentration-time curve (AUC) by 1.55-, 1.74- and 1.80-fold, respectively, in each of these groups compared to placebo. The AUC ratio of lansoprazole to lansoprazole sulphone, which is considered an index of CYP450 3A4 activity, was significantly increased by clarithromycin in all three groups. However, elimination half-life of lansoprazole was prolonged by 1.54-fold only in PMs. Mild diarrhea was reported in two subjects and mild abdominal disturbance in six subjects during clarithromycin coadministration. These side effects continued until day 6 and ameliorated the day after discontinuation of clarithromycin, whereas no adverse events were reported during placebo administration or after lansoprazole plus placebo. In another study, clarithromycin induced dose-dependent increases in the plasma concentration of lansoprazole in a group of 20 patients receiving treatment for H. pylori eradication. Mean 3-hour plasma lansoprazole concentration was 385 ng/mL for the control subjects who received lansoprazole 30 mg and amoxicillin 750 mg twice a day for 7 days; 696 ng/mL for patients coadministered clarithromycin 200 mg twice a day; and 947 ng/mL for patients coadministered clarithromycin 400 mg twice a day.

MANAGEMENT: Although lansoprazole is generally well tolerated, caution may be advised during coadministration with clarithromycin, particularly if higher dosages of one or both drugs are used. Dosage adjustment may be necessary in patients who experience excessive adverse effects of lansoprazole.

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Although some in vitro data indicate synergism between macrolide antibiotics and penicillins, other in vitro data indicate antagonism. When these drugs are given together, neither has predictable therapeutic efficacy. Data are available for erythromycin, although theoretically this interaction could occur with any macrolide. Except for monitoring of the effectiveness of antibiotic therapy, no special precautions appear to be necessary.

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