Drug Interactions between Omeclamox-Pak and pazopanib

GENERALLY AVOID: Coadministration with potent inhibitors of CYP450 3A4 may significantly increase the plasma concentrations of pazopanib, which is primarily metabolized by the isoenzyme. In healthy subjects, administration of a single dose of pazopanib eye drop with the potent CYP450 3A4 inhibitor ketoconazole resulted in a 150% increase in pazopanib peak plasma concentration (Cmax) and a 220% increase in systemic exposure (AUC). Although not studied, the interaction may increase the risk of QT interval prolongation and torsade de pointes arrhythmia as well as severe and fatal hepatotoxicity associated with the use of pazopanib.

MANAGEMENT: Concomitant use of pazopanib with potent CYP450 3A4 inhibitors should generally be avoided. Some authorities recommend avoiding concomitant use of pazopanib during and for 2 weeks after treatment with itraconazole. If coadministration is unavoidable, a reduction of the pazopanib dosage to 400 mg once daily should be considered. Based on pharmacokinetic studies, this dosage is predicted to adjust the pazopanib systemic exposure (AUC) to the range observed without inhibitors. However, clinical data are lacking. Patients should have liver function tests (ALT, AST, bilirubin), electrocardiograms, and serum electrolyte levels performed at baseline and regular intervals as recommended in the product labeling. Further dosage reductions may be needed if adverse effects occur during therapy. Patients should be advised to notify their physician if they experience 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 seek medical attention if they experience symptoms that could indicate the occurrence of torsade de pointes such as dizziness, palpitations, or syncope. Following discontinuation of the potent CYP450 3A4 inhibitor, a washout period of approximately one week should be allowed before the pazopanib dosage is adjusted upward.

GENERALLY AVOID: Coadministration with proton pump inhibitors or H2-receptor antagonists may significantly decrease the oral bioavailability of pazopanib and reduce its concentrations in plasma. The solubility of pazopanib is pH-dependent, thus an increase in pH may interfere with its absorption. According to the product labeling, pazopanib is very slightly soluble at pH 1 and practically insoluble above pH 4 in aqueous media. When pazopanib (800 mg once daily in the morning) was coadministered with esomeprazole (40 mg once daily in the evening) for 5 days in 12 patients with advanced solid tumors, mean steady-state pazopanib peak plasma concentration (Cmax) and systemic exposure (AUC) decreased by approximately 40% each. The AUCs of three metabolites were also decreased. Mean steady-state trough concentration of pazopanib was reduced to 17.3 mcg/mL, which is close to the reported threshold of >=15 mcg/mL for clinical efficacy as suggested by a phase I trial of pazopanib. However, the potential for subtherapeutic pazopanib exposure in some patients cannot be excluded.

MANAGEMENT: Concomitant use of pazopanib with proton pump inhibitors and H2-receptor antagonists should generally be avoided. If acid-suppression therapy is required, short-acting antacids should be considered, with dosing separated by several hours from pazopanib dosing. Some experts recommend administering pazopanib at least 1 hour before or 2 hours after antacids. Alternatively, a group of Dutch clinical pharmacologists and the EMA (European Medicines Agency) suggest that pazopanib may be given with a proton pump inhibitor, when necessary, if pazopanib is administered without food once daily in the evening concomitantly with the proton pump inhibitor. This recommendation is based on physiological considerations rather than actual clinical data. Since gastric pH has been reported to be lowest just before dinner in patients treated with esomeprazole daily in the evening, the thought is that impact on pazopanib solubility and absorption should be minimized when pazopanib is also administered in the evening. Similarly, when coadministration with an H2-receptor antagonist is required, it has been recommended that pazopanib be taken without food at least 2 hours before or 10 hours after a dose of the H2-receptor antagonist.

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.

Clarithromycin may increase and prolong the omeprazole plasma concentration. The mechanism may be related to clarithromycin inhibition of hepatic cytochrome P450 enzymes responsible for omeprazole metabolism. Coadministration of omeprazole may result in an increase in clarithromycin and 14-(R)-hydroxyclarithromycin plasma concentrations. These increases may be due to the effect of omeprazole on gastric pH.