Apo-Dasatinib Drug Interactions

Overview: Dasatinib is an inhibitor of CYP3A4 and may decrease the metabolic clearance of drugs that are primarily metabolized by CYP3A4. At clinically relevant concentrations, dasatinib does not inhibit CYP 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, or 2E1. Dasatinib is not an inducer of CYP enzymes.
Drug-Drug Interactions: Drugs that may increase dasatinib plasma concentrations: CYP3A4 Inhibitors: In vitro studies indicate that dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg dasatinib once daily co-administered with 200 mg of ketoconazole BID increased the dasatinib C_max and AUC by four- and five-fold, respectively. Substances that inhibit CYP3A4 activity (eg, ketoconazole, itraconazole, erythromycin, clarithromycin, grapefruit juice) may decrease metabolism and increase concentrations of dasatinib and should be avoided. Selection of an alternate concomitant medication with no or minimal CYP3A4 inhibition potential is recommended. If systemic administration of a potent CYP3A4 inhibitor cannot be avoided, a dose reduction should be considered and the patient should be closely monitored for toxicity (see Drug-Food Interactions as follows, Precautions, and Dosage & Administration).
Drugs that may decrease dasatinib plasma concentrations: CYP3A4 Inducers: Data from a study of 20 healthy subjects indicate that when a single morning dose of dasatinib was administered following 8 days of continuous evening administration of 600 mg of rifampicin, a potent CYP3A4 inducer, the mean C_max and AUC of dasatinib were decreased by 81% and 82%, respectively. In addition, more healthy male subjects experienced increases in QTcF of >30 msec from the baseline recordings when a single dose of dasatinib was administered 12 hours following rifampicin compared to when dasatinib was given alone (25% vs. 10%, n=20). No subject experienced QTcF >450 msec or a change from baseline ≥60 msec (see Precautions).
Antacids: Nonclinical data indicate that dasatinib has pH dependent solubility. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50 mg dose of dasatinib was associated with no relevant change in dasatinib AUC or C_max. On the contrary, when 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50 mg dose of dasatinib, a 55% reduction in dasatinib AUC and a 58% reduction in C_max were observed (see Precautions).
Famotidine: In a study of 24 healthy subjects, administration of a single 50 mg dose of dasatinib 10 hours following famotidine reduced the AUC and C_max of dasatinib by 61% and 63%, respectively (see Precautions).
Drugs that may have their plasma concentration altered by dasatinib: CYP3A4 Substrates: Single dose data from a study of 54 healthy subjects indicate that the mean C_max and AUC of simvastatin, a prototypical CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin (80 mg) was administered in combination with a single 100 mg dose of dasatinib. In addition, three healthy subjects (n=48) experienced QTcF of >30 msec from the baseline ECG recordings following the concomitant use of a single dose of simvastatin and dasatinib. No subject experienced QTcF >450 msec or a change from baseline >60 msec. The effect of CYP3A4 substrates on the pharmacokinetics of dasatinib has not been studied (see Precautions).
Drugs that prolong QTc interval or induce torsades de pointes: The concomitant use of dasatinib with medicinal products known to prolong QTc interval or medicinal products able to induce torsades de pointes should be avoided if possible. Medicinal products that are generally accepted to carry the risk of QT prolongation and torsades de pointes include but are not limited to the examples that follow: Class IA (e.g. disopyramide, procainamide), Class III (e.g. amiodarone, sotalol, ibutilide), or Class IC (e.g. flecainide) antiarrhythmic medicinal products, antipsychotics (e.g. chlorpromazine, haloperidol, pimozide), opioids (e.g. methadone), macrolide antibiotics (e.g. erythromycin, clarithromycin), quinolone antibiotics (e.g. moxifloxacin), antimalarials (e.g. chloroquine), GI stimulants or others (e.g. domperidone).
Drug-Food Interactions: APO-DASATINIB should not be taken with grapefruit or grapefruit juice.
Drug-Herb Interactions: Concomitant use of dasatinib and St John's Wort (Hypericum perforatum) may substantially reduce exposure to dasatinib.