Interactions : אינטראקציות

4.5 Interaction with other medicinal products and other forms of interaction
Pharmacokinetic interactions
Effect of vandetanib on other medicinal products
In healthy subjects, the exposure for midazolam (CYP3A4 substrate) was not affected when given together with a single dose of vandetanib at 800 mg.

Vandetanib is an inhibitor of the organic cation 2 (OCT2) transporter. In healthy subjects with wild type for OCT2, the AUC(0-t) and Cmax for metformin (OCT2 substrate) were increased by 74% and 50%, respectively and CLR of metformin was decreased by 52% when given together with vandetanib. Appropriate clinical and/or laboratory monitoring is recommended for patients receiving concomitant metformin and vandetanib, and such patients may require a lower dose of metformin.

In healthy subjects, the AUC(0-t) and Cmax for digoxin (P-gp substrate) were increased by 23% and 29 % respectively, when given together due to P-gp inhibition by vandetanib. Furthermore, the bradycardiac effect of digoxin may increase the risk of vandetanib QTc interval prolongation and Torsade de Pointes. Therefore, an appropriate clinical (e.g. ECG) and/or laboratory monitoring is recommended for patients receiving concomitant digoxin and vandetanib, and such patients may require a lower dose of digoxin. (For vandetanib monitoring, see section 4.2 Posology and Method of administration and section 4.4 Special warnings and precautions for use).

As regards other P-gp substrates such as dabigatran, a clinical monitoring is recommended in case of combination with vandetanib.
Effect of other medicinal products on vandetanib
In healthy subjects, no clinically significant interaction was shown between vandetanib (a single dose of 300mg) and the potent CYP3A4 inhibitor, itraconazole (repeated doses of 200mg once daily). In healthy male subjects, the exposure to vandetanib was reduced by 40% when given together with the potent CYP3A4 inducer, rifampicin. Administration of vandetanib with potent CYP3A4 inducers should be avoided.

In healthy subjects, the Cmax for vandetanib was decreased by 15% while the AUC(0-t) for vandetanib was not affected when given together with omeprazole. Neither the Cmax nor the AUC(0-t) for vandetanib was affected when given together with ranitidine. Therefore, no change in dose of vandetanib is required when vandetanib is given with either omeprazole or ranitidine.
Pharmacodynamic interactions
Biliary excretion of unchanged vandetanib is one of the excretion pathways for vandetanib.
Vandetanib is not a substrate of multidrug resistance protein 2 (MRP2), p-glycoprotein (P-gp) or breast cancer resistance protein (BCRP).

Medicinal products known to prolong QTc interval
Vandetanib has been shown to prolong the ECG QTc interval; Torsades de pointes have been uncommonly reported. Therefore the concomitant use of vandetanib with medicinal products known to also prolong the QTc interval and/or induce Torsades de pointes is either contraindicated or not recommended depending on existing alternative therapies.
• Combinations contraindicated (see section 4.3): Cisapride, erythromycin intravenous (IV), toremifene, mizolastine, moxifloxacin, arsenic, Class IA and III antiarrhythmics
• Combinations not recommended: Methadone, haloperidol, amisulpride, chlorpromazine, sulpiride, zuclopenthixol, halofantrine, pentamidine and lumefantrine.

If there is no appropriate alternative therapy, not recommended combinations with vandetanib may be made with additional ECG monitoring of the QTc interval, evaluation of electrolytes and further control at onset or worsening of diarrhoea.

Results of a pharmacodynamic and pharmacokinetic interaction study indicated that co- administration with ondansetron in healthy patients appeared to have little effect on the pharmacokinetics of vandetanib, but had a small additive effect on the prolongation of the QTc interval of approximately 10 ms. Therefore, the concomitant use of ondansetron with vandetanib is not recommended. If ondansetron is administered with vandetanib, closer monitoring of serum electrolytes and ECGs and aggressive management of any abnormalities is required.


Vitamin K antagonists
Due to the increased thrombotic risk in patients with cancer, the use of anticoagulation is frequent. In consideration of the high intra-individual variability of the response to anticoagulation, and the possibility of interaction between vitamin K antagonists and chemotherapy, an increased frequency of the INR (International Normalised Ratio) monitoring is recommended, if it is decided to treat the patient with vitamin K antagonists.