Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Interaction studies have only been performed in adults.
Erlotinib and other CYP substrates
Erlotinib is a potent inhibitor of CYP1A1, and a moderate inhibitor of CYP3A4 and CYP2C8, as well as a strong inhibitor of glucuronidation by UGT1A1 in vitro.
The physiological relevance of the strong inhibition of CYP1A1 is unknown due to the very limited expression of CYP1A1 in human tissues.

When erlotinib was co-administered with ciprofloxacin, a moderate CYP1A2 inhibitor, the erlotinib exposure [AUC] increased significantly by 39%, while no statistically significant change in Cmax was found. Similarly, the exposure to the active metabolite increased by about 60% and 48% for AUC and Cmax, respectively. The clinical relevance of this increase has not been established. Caution should be exercised when ciprofloxacin or potent CYP1A2 inhibitors (e.g. fluvoxamine) are combined with erlotinib. If adverse reactions related to erlotinib are observed, the dose of erlotinib may be reduced.
Pre-treatment or co-administration of Tarceva did not alter the clearance of the prototypical CYP3A4 substrates, midazolam and erythromycin, but did appear to decrease the oral bioavailability of midazolam by up to 24%. In another clinical study, erlotinib was shown not to affect pharmacokinetics of the concomitantly administered CYP3A4/2C8 substrate paclitaxel. Significant interactions with the clearance of other CYP3A4 substrates are therefore unlikely.

The inhibition of glucuronidation may cause interactions with medicinal products which are substrates of UGT1A1 and exclusively cleared by this pathway. Patients with low expression levels of UGT1A1 or genetic glucuronidation disorders (e.g. Gilbert’s disease) may exhibit increased serum concentrations of bilirubin and must be treated with caution.

Erlotinib is metabolised in the liver by the hepatic cytochromes in humans, primarily CYP3A4 and to a lesser extent by CYP1A2. Extrahepatic metabolism by CYP3A4 in intestine, CYP1A1 in lung, and CYP1B1 in tumour tissue also potentially contribute to the metabolic clearance of erlotinib. Potential interactions may occur with active substances which are metabolised by, or are inhibitors or inducers of, these enzymes.

Potent inhibitors of CYP3A4 activity decrease erlotinib metabolism and increase erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib with ketoconazole (200 mg orally twice daily for 5 days), a potent CYP3A4 inhibitor, resulted in an increase of erlotinib exposure (86% of AUC and 69% of Cmax). Therefore, caution should be used when erlotinib is combined with a potent CYP3A4 inhibitor, e.g. azole antifungals (i.e. ketoconazole, itraconazole, voriconazole), protease inhibitors, erythromycin or clarithromycin. If necessary the dose of erlotinib should be reduced, particularly if toxicity is observed.

Potent inducers of CYP3A4 activity increase erlotinib metabolism and significantly decrease erlotinib plasma concentrations. In a clinical study, the concomitant use of erlotinib and rifampicin (600 mg orally once daily for 7 days), a potent CYP3A4 inducer, resulted in a 69% decrease in the median erlotinib AUC.
Co-administration of rifampicin with a single 450 mg dose of Tarceva resulted in a mean erlotinib exposure (AUC) of 57.5% of that after a single 150 mg Tarceva dose in the absence of rifampicin treatment. Co- administration of Tarceva with CYP3A4 inducers should therefore be avoided. For patients who require concomitant treatment with Tarceva and a potent CYP3A4 inducer such as rifampicin an increase in dose to 300 mg should be considered while their safety (including renal and liver functions and serum electrolytes) is closely monitored, and if well tolerated for more than 2 weeks, further increase to 450 mg could be considered with close safety monitoring. Reduced exposure may also occur with other inducers e.g. phenytoin, carbamazepine, barbiturates or St. John’s Wort (hypericum perforatum). Caution should be observed when these active substances are combined with erlotinib. Alternate treatments lacking potent CYP3A4 inducing activity should be considered when possible.

Erlotinib and coumarin-derived anticoagulants
Interaction with coumarin-derived anticoagulants including warfarin leading to increased International Normalized Ratio (INR) and bleeding events, which in some cases were fatal, have been reported in patients receiving Tarceva. Patients taking coumarin-derived anticoagulants should be monitored regularly for any changes in prothrombin time or INR.

Erlotinib and statins
The combination of Tarceva and a statin may increase the potential for statin-induced myopathy, including rhabdomyolysis, which was observed rarely.

Erlotinib and smokers
Results of a pharmacokinetic interaction study indicated a significant 2.8-, 1.5- and 9-fold reduced AUCinf, Cmax and plasma concentration at 24 hours, respectively, after administration of Tarceva in smokers as compared to non-smokers. Therefore, patients who are still smoking should be encouraged to stop smoking as early as possible before initiation of treatment with Tarceva, as plasma erlotinib concentrations are reduced otherwise. Based on the data from the CURRENTS study, no evidence was seen for any benefit of a higher erlotinib dose of 300 mg when compared with the recommended dose of 150 mg in active smokers. Safety data were comparable between the 300 mg and 150 mg doses; however, there was a 
numerical increase in the incidence of rash, interstitial lung disease and diarrhoea, in patients receiving the higher dose of erlotinib (see sections 4.2, 4.4, 5.1 and 5.2).

Erlotinib and P-glycoprotein inhibitors
Erlotinib is a substrate for the P-glycoprotein active substance transporter. Concomitant administration of inhibitors of Pgp, e.g. cyclosporine and verapamil, may lead to altered distribution and/or altered elimination of erlotinib. The consequences of this interaction for e.g. CNS toxicity have not been established. Caution should be exercised in such situations.

Erlotinib and medicinal products altering pH
Erlotinib is characterised by a decrease in solubility at pH above 5. Medicinal products that alter the pH of the upper Gastro-Intestinal (GI) tract may alter the solubility of erlotinib and hence its bioavailability. Co- administration of erlotinib with omeprazole, a proton pump inhibitor (PPI), decreased the erlotinib exposure [AUC] and maximum concentration [Cmax] by 46% and 61%, respectively. There was no change to Tmax or half-life. Concomitant administration of Tarceva with 300 mg ranitidine, an H2-receptor antagonist, decreased erlotinib exposure [AUC] and maximum concentrations [Cmax] by 33% and 54%, respectively. Increasing the dose of Tarceva when co-administered with such agents is not likely to compensate for this loss of exposure. However, when Tarceva was dosed in a staggered manner 2 hours before or 10 hours after ranitidine 150 mg b.i.d., erlotinib exposure [AUC] and maximum concentrations [Cmax] decreased only by 15% and 17%, respectively. The effect of antacids on the absorption of erlotinib has not been investigated but absorption may be impaired, leading to lower plasma levels. In summary, the combination of erlotinib with proton pump inhibitors should be avoided. If the use of antacids is considered necessary during treatment with Tarceva, they should be taken at least 4 hours before or 2 hours after the daily dose of Tarceva. If the use of ranitidine is considered, it should be used in a staggered manner; i.e.
Tarceva must be taken at least 2 hours before or 10 hours after ranitidine dosing.

Erlotinib and Gemcitabine
In a Phase Ib study, there were no significant effects of gemcitabine on the pharmacokinetics of erlotinib nor were there significant effects of erlotinib on the pharmacokinetics of gemcitabine.

Erlotinib and Carboplatin/Paclitaxel
Erlotinib increases platinum concentrations. In a clinical study, the concomitant use of erlotinib with carboplatin and paclitaxel led to an increase of total platinum AUC0-48 of 10.6%. Although statistically significant, the magnitude of this difference is not considered to be clinically relevant. In clinical practice, there may be other co-factors leading to an increased exposure to carboplatin like renal impairment. There were no significant effects of carboplatin or paclitaxel on the pharmacokinetics of erlotinib.

Erlotinib and Capecitabine
Capecitabine may increase erlotinib concentrations. When erlotinib was given in combination with capecitabine, there was a statistically significant increase in erlotinib AUC and a borderline increase in C max when compared with values observed in another study in which erlotinib was given as single agent. There were no significant effects of erlotinib on the pharmacokinetics of capecitabine.

Erlotinib and proteasome inhibitors
Due to the working mechanism, proteasome inhibitors including bortezomib may be expected to influence the effect of EGFR inhibitors including erlotinib. Such influence is supported by limited clinical data and preclinical studies showing EGFR degradation through the proteasome.