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Interactions with erlotinib and gefitinib

By Rhoda Lee and Julia Sawyer

SmokingThe Stockley editorial team discusses emerging interactions with two recent oral medicines for lung cancer


Lung cancer is responsible for more than 33,500 deaths every year in the UK — more than breast cancer, prostate cancer and leukaemia combined. The prognosis for lung cancer remains poor, and there is continued interest in developing new and more targeted therapies.

One such class of drugs is the tyrosine kinase inhibitors, of which erlotinib and gefitinib are currently licensed for the treatment of locally advanced or metastatic non-small cell lung cancer. Both drugs act by inhibiting the tyrosine kinase activity of the epidermal growth factor receptor.

It is important to be aware of interactions that can lead to a reduction in erlotinib (Tarceva) and gefitinib (Iressa) levels, increasing the risk of treatment failure. But equally, because both these anticancer drugs are associated with serious adverse effects, any drug that might increase their levels could increase toxicity.

It is also important, therefore, to be aware of these interactions and how best to manage them. Drug interactions affecting erlotinib and gefitinib levels occur by two main mechanisms: altered absorption or altered metabolism.

Drug absorption interactions

The absorption of erlotinib and gefitinib is pH dependent, with reduced absorption at higher gastric pH. So any drug that increases gastric pH, such as proton pump inhibitors, H2-receptor antagonists and antacids, could reduce their absorption. For example, omeprazole has been shown almost to halve exposure to erlotinib. Because proton pump inhibitors cause such a potent, long-acting reduction in gastric acid, their concurrent use with erlotinib or gefitinib should be avoided.

Ranitidine has also been found to reduce exposure to erlotinib by about a third when taken at the same time; but separating the doses appeared to minimise the interaction. Therefore, erlotinib may be taken towards the end of the ranitidine dosing interval when its levels and effects are lowest (ie, 10 hours after a dose of ranitidine and two hours before the next).

Ranitidine also nearly halves exposure to gefitinib, and because there are no data to indicate that separating the doses might reduce this interaction, it would seem prudent to avoid concurrent use.

Antacids are generally much shorter acting than proton pump inhibitors or H2-receptor antagonists, and may be given to patients taking erlotinib or gefitinib as long as they are not taken in the four hours before or two hours after taking an erlotinib or gefitinib dose.

Drug metabolism interactions

In common with many of the tyrosine kinase inhibitors, erlotinib and gefitinib are metabolised by the cytochrome P450 isoenzyme CYP3A4. In addition, erlotinib is metabolised by CYP1A2 and gefitinib by CYP2D6. Therefore drugs that affect the metabolism of erlotinib and gefitinib by these isoenzymes can result in clinically important drug interactions.


Ketoconazole and itraconazole (both known potent inhibitors of CYP3A4) modestly increase exposure to erlotinib and gefitinib by about 70 per cent and so the concurrent use of these azoles should be closely monitored for an increase in erlotinib or gefitinib adverse effects such as skin rash and diarrhoea. Similar precautions are warranted with any other potent CYP3A4 inhibitors.

Conversely, rifampicin (a potent enzyme inducer) has been shown to decrease erlotinib and gefitinib exposure markedly — so much so, that it is likely that standard doses of these tyrosine kinase inhibitors would no longer be effective if rifampicin were used concurrently, and treatment failure would be likely.

The manufacturers report that trebling the erlotinib dose still resulted in a 43 per cent lower exposure in the presence of rifampicin. Similarly, the enzyme-inducing antiepileptics (eg, carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital and primidone) can markedly increase the metabolism of erlotinib.

In one study, the exposure to erlotinib at 400 to 500mg daily was reported to be similar to erlotinib alone at 100 to 150mg daily when given to patients taking these antiepileptic drugs. Where possible, the use of enzyme-inducing drugs should be avoided in patients taking erlotinib or gefitinib.

If concurrent use is essential, the dose of erlotinib or gefitinib should be increased as tolerated. In patients already taking enzyme-inducing antiepileptics, starting doses of 300 to 500mg daily have been suggested for erlotinib, and 500mg daily has been suggested for gefitinib.


Altering the metabolism of erlotinib by CYP1A2 is also clinically important. Tobacco smoke is a known inducer of CYP1A2 and patients who smoke have markedly reduced exposure to erlotinib (about half to two-thirds lower) and respond less well to treatment than non-smokers. Smoking status should, therefore, be considered when using erlotinib.

Smokers should be encouraged to stop smoking before starting erlotinib and, in those who continue to smoke, the erlotinib dose should be cautiously increased as tolerated. Conversely, potent inhibitors of CYP1A2 (eg, fluvoxamine) are predicted to increase the exposure to erlotinib. Concurrent use should be closely monitored for an increase in erlotinib adverse effects.


As with smoking status for erlotinib, CYP2D6 metaboliser phenotype (that is, the patient’s genetically determined levels of active CYP2D6) may also be a factor in determining exposure to gefitinib, although the evidence is less clear.

There is some evidence of increased gefitinib exposure in those with the poor metaboliser phenotype. This suggests that, inhibiting CYP2D6 in patients with normal levels of this isoenzyme (the majority of the population) could result in an increase in gefitinib exposure.

Therefore if a drug that is a potent inhibitor of CYP2D6 (eg, fluoxetine, paroxetine) is required in any patient taking gefitinib it would seem sensible to monitor for an increase in adverse effects.


Erlotinib and gefitinib are useful treatment options for lung cancer. Nevertheless, it is important to remember that drug interactions may have a clinically relevant effect on their efficacy or toxicity and dose adjustments of these drugs may be needed to accommodate any interactions.

StockleyThis article has been produced by Rhoda Lee and Julia Sawyer, on behalf of the Stockley editorial team.

The 9th edition of “Stockley’s drug interactions” (May 2010), is now available in print, CD-ROM and at MedicinesComplete from the Pharmaceutical Press.

Citation: The Pharmaceutical Journal URI: 11067716

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