Key messages
- In a prospective study of 302 patients starting anticancer treatment, 120 potentially clinically relevant interactions were found in 81 patients; the treating oncologist had already intervened in 13% of patients and a clinical pharmacologist proposed an intervention in another 14% [2].
- Many oral targeted drugs, such as dasatinib and ibrutinib, are metabolised by CYP3A: strong inhibitors (ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, ritonavir) raise their levels and strong inducers (rifampicin, carbamazepine, phenytoin, enzalutamide, apalutamide) lower them [1].
- Venetoclax with posaconazole: in CLL it is contraindicated at initiation and during the ramp-up, after which the dose becomes 70 mg; in AML the doses on days 1 to 4 are 10, 20, 50 and 70 mg [3].
- Omeprazole reduces the absorption of erlotinib and dasatinib and concomitant use is not recommended; by contrast, the absorption of osimertinib and palbociclib tablets did not change with acid suppressants [5, 6, 7, 8].
- Capecitabine raises the INR of patients on warfarin, and this risk is in the label's boxed warning; check the INR frequently during capecitabine and after it is stopped; INR rises have sometimes occurred up to one month after stopping [10].
- Methotrexate reaches higher levels with omeprazole, non-steroidal anti-inflammatory drugs, penicillins and sulfonamides [11]; an apixaban dose of 5 or 10 mg twice daily is halved with combined P-gp and strong CYP3A4 inhibitors, and apixaban should not be used with combined inducers of both [12].
Oral chemotherapy drug interactions: simple tips for patients
Cancer tablets can also interact with some medicines, foods and supplements. Some medicines raise the amount of the cancer drug in the blood and make its side effects worse. Others lower the amount, and the treatment may then work less well [1].
- Antifungal medicines and some antibiotics: antifungal medicines such as ketoconazole, itraconazole and posaconazole, and the antibiotic clarithromycin, raise the amount of many cancer tablets [1].
- The TB drug and epilepsy medicines: the tuberculosis drug rifampicin and the epilepsy medicines carbamazepine and phenytoin lower the amount of these tablets [1].
- Stomach tablets: tablets such as omeprazole and pantoprazole reduce the absorption of some cancer tablets, such as erlotinib and dasatinib [5, 6].
- The blood thinner warfarin: if you take warfarin and start capecitabine, your blood clotting test (INR) needs to be checked sooner and more often [10].
- What interacts with apixaban? The antifungal medicines ketoconazole and itraconazole and the HIV medicine ritonavir raise the amount of apixaban and increase the risk of bleeding. Rifampicin, carbamazepine and phenytoin weaken it. Aspirin and anti-inflammatory painkillers such as ibuprofen also raise the risk of bleeding [12].
- Grapefruit: the official leaflets of venetoclax, ibrutinib and dasatinib say not to eat grapefruit [3, 4, 5]. Read more about grapefruit and Seville oranges.
One simple step: show your doctor or pharmacist a list of all your medicines, drops, supplements and over-the-counter products at every visit. In one study, the more over-the-counter medicines a patient took, the more interactions needed action [2]. Do not add or stop a medicine without advice.
When should I call my doctor?
- Another doctor has prescribed an antibiotic or an antifungal medicine: call your cancer doctor before the first tablet; sometimes the dose of the cancer tablet must be lowered or stopped for a few days [3, 4].
- While taking apixaban or warfarin: red, pink or brown urine, red or black stools, vomiting blood, coughing up blood, nosebleeds or bleeding gums that will not stop, or unexplained bruising [10, 12].
- While taking ribociclib: a pounding heartbeat, an irregular heartbeat, dizziness or fainting [9].
- For heavy bleeding or fainting, call your local emergency number.
Oral chemotherapy drug interactions: why and how they happen
Interactions have three main mechanisms: altered drug metabolism and transport (especially through CYP3A and P-gp), altered gastrointestinal absorption (for example when gastric pH rises) and pharmacodynamic interactions (such as additive effects on the QT interval or on bleeding risk). Higher exposure can cause toxicity and lower exposure can reduce efficacy [1, 9, 12].
FDA definitions of inhibitor and inducer strength, based on the change in the AUC of a sensitive substrate: a strong inhibitor increases the AUC at least 5-fold, a moderate one 2-fold to less than 5-fold and a weak one 1.25-fold to less than 2-fold; a strong inducer decreases the AUC by at least 80%, a moderate one by 50% to less than 80% and a weak one by 20% to less than 50% [1].
The anticancer drug itself is sometimes the perpetrator: imatinib and crizotinib are moderate CYP3A inhibitors, idelalisib, ceritinib and tucatinib are strong CYP3A inhibitors, and enzalutamide, apalutamide and mitotane are strong CYP3A inducers [1]. Ribociclib 400 mg increased the AUC of midazolam 3.8-fold [9], and venetoclax raises the levels of warfarin and of P-gp substrates [3].
In the prospective Rotterdam study, the number of comorbidities and the number of over-the-counter drugs were determinants of the need for an intervention, and the authors recommended structured interaction screening before and during anticancer treatment, with oncologists working closely with clinical pharmacologists [2].
CYP3A4 inhibitors and inducers list, with P-gp inhibitors
| Group | Examples | Effect on a sensitive substrate |
|---|---|---|
| Strong CYP3A inhibitor | Ketoconazole, itraconazole, posaconazole, voriconazole, clarithromycin, telithromycin, ritonavir, cobicistat, nefazodone; anticancer drugs: idelalisib, ceritinib, tucatinib, adagrasib | AUC increase of at least 5-fold [1] |
| Moderate CYP3A inhibitor | Fluconazole, isavuconazole, erythromycin, ciprofloxacin, diltiazem, verapamil, dronedarone, aprepitant, grapefruit juice; anticancer drugs: imatinib, crizotinib | AUC increase of 2-fold to less than 5-fold [1] |
| Strong CYP3A inducer | Rifampicin, carbamazepine, phenytoin; anticancer drugs: enzalutamide, apalutamide, mitotane, ivosidenib | AUC decrease of at least 80% [1] |
| Moderate CYP3A inducer | Phenobarbital, primidone, efavirenz, bosentan, cenobamate; anticancer drugs: dabrafenib, lorlatinib, sotorasib | AUC decrease of 50% to less than 80% [1] |
| P-gp inhibitor | Amiodarone, verapamil, dronedarone, quinidine, ranolazine, ciclosporin, clarithromycin, erythromycin, itraconazole, ketoconazole; anticancer drugs: lapatinib, tucatinib, capmatinib | AUC increase of dabigatran, digoxin or edoxaban of at least 1.5-fold [1] |
The FDA list gives examples and is not complete; the effect of grapefruit juice depends on its type and amount, and it is sometimes as strong as a strong inhibitor [1]. For each drug, also check the interaction section of its label.
Dose changes for oral anticancer drugs with CYP3A inhibitors and inducers (including venetoclax with posaconazole)
| Drug (usual dose) | With a strong CYP3A inhibitor | With a moderate CYP3A inhibitor or a P-gp inhibitor | With a CYP3A inducer |
|---|---|---|---|
| Venetoclax in CLL (400 mg daily) | Contraindicated at initiation and during the 5-week ramp-up; afterwards consider an alternative first, otherwise 70 mg daily with posaconazole and 100 mg daily with other strong inhibitors [3] | Reduce the dose by at least 50%; after the ramp-up, consider an alternative first [3] | Strong or moderate: avoid [3] |
| Venetoclax in AML (400 mg with azacitidine or decitabine) | With posaconazole, days 1 to 4: 10, 20, 50 and 70 mg, then 70 mg daily; with other strong inhibitors: 10, 20, 50 and 100 mg, then 100 mg daily [3] | Reduce the dose by at least 50% [3] | Strong or moderate: avoid [3] |
| Ibrutinib in B-cell malignancies (420 mg daily in CLL) | Voriconazole 200 mg twice daily or posaconazole suspension 100 mg once or twice daily or 200 mg twice daily: 140 mg; posaconazole suspension 200 mg three times daily or 400 mg twice daily, or intravenous posaconazole or delayed-release tablets 300 mg daily: 70 mg; other strong inhibitors: avoid, and interrupt ibrutinib for short-term use (7 days or less) [4] | Moderate inhibitor: 280 mg daily [4] | Strong: avoid [4] |
| Dasatinib (100 or 140 mg daily) | Avoid; if unavoidable: 140 to 40 mg, 100 to 20 mg and 70 to 20 mg daily; at 60 or 40 mg, interrupt until the inhibitor is stopped; increase the dose about 1 week after stopping the inhibitor [5] | No separate recommendation in the label [5] | Strong: avoid; if unavoidable, increase the dose with close monitoring for toxicity [5] |
| Erlotinib (150 or 100 mg daily) | Avoid if possible; for severe adverse reactions reduce in 50 mg steps; the same applies to ciprofloxacin, which inhibits both CYP3A4 and CYP1A2 [6] | No separate recommendation in the label [6] | Avoid if possible; if unavoidable, increase in 50 mg steps every 2 weeks up to a maximum of 450 mg; in smokers increase up to a maximum of 300 mg and return to the usual dose immediately after quitting [6] |
| Osimertinib (80 mg daily) | No clinically significant effect; itraconazole raised the AUC by only 24% [7] | No separate recommendation in the label [7] | Strong: avoid; if unavoidable 160 mg daily, returning to 80 mg 3 weeks after the inducer is stopped; no dose change with moderate or weak inducers [7] |
| Palbociclib (125 mg daily) | Avoid; if unavoidable 75 mg daily, returning to the previous dose after 3 to 5 half-lives of the inhibitor; itraconazole raised the AUC by 87% [8] | No separate recommendation in the label [8] | Strong: avoid; rifampicin lowered the AUC by 85% [8] |
| Ribociclib (600 mg in advanced disease, 400 mg in early breast cancer) | Avoid; if unavoidable: 400 mg daily in advanced disease and 200 mg daily in early breast cancer; return to the previous dose after at least 5 half-lives of the inhibitor [9] | No separate recommendation in the label; modelling predicts that erythromycin raises the AUC only 1.1- to 1.2-fold [9] | Strong: avoid [9] |
After the inhibitor is stopped, venetoclax returns to the previous dose 2 to 3 days later and ibrutinib once the inhibitor has been discontinued [3, 4].
- Ketoconazole increased venetoclax Cmax by 130% and AUC by 540%; posaconazole 300 mg with venetoclax 50 mg and 100 mg gave an AUC 90% and 144% higher, respectively, than venetoclax 400 mg alone; multiple-dose rifampicin lowered the AUC by 71% [3].
- Ketoconazole increased the AUC of ibrutinib 24-fold, voriconazole 5.7-fold and erythromycin 3-fold; rifampicin decreased the AUC more than 10-fold [4].
- Ketoconazole increased the AUC of dasatinib 5-fold and rifampicin lowered it by 82% [5]; rifampicin lowered the AUC of osimertinib by 78% [7].
- Grapefruit: the labels of venetoclax (together with Seville oranges and starfruit), ibrutinib (together with Seville oranges), dasatinib and palbociclib advise avoiding it [3, 4, 5, 8].
For imatinib, nilotinib, abemaciclib and olaparib, see the interaction section of each drug page: imatinib, nilotinib, abemaciclib and olaparib. Dose adjustment in kidney and liver impairment is covered in a separate lesson.
Tyrosine kinase inhibitors and PPIs: omeprazole and other acid suppressants
| Drug | Effect of the acid suppressant | Label recommendation |
|---|---|---|
| Erlotinib | Omeprazole: AUC down 46% and Cmax down 61%; ranitidine 300 mg 2 hours before erlotinib: AUC down 33%; with correct spacing, ranitidine 150 mg twice daily lowered the AUC by only 15% [6] | PPI: avoid if possible, because spacing does not remove the interaction and increasing the erlotinib dose does not make up the lost exposure; H2 antagonist: erlotinib 10 hours after it and at least 2 hours before the next dose; antacid: separate by several hours [6] |
| Dasatinib | Famotidine 10 hours before dasatinib: AUC down 61%; omeprazole 40 mg 22 hours before: AUC down 43%; antacid at the same time: AUC down 55%, but no relevant change in AUC when given 2 hours before [5] | Do not use H2 antagonists or PPIs; use an antacid instead, at least 2 hours before or after dasatinib [5] |
| Osimertinib | Omeprazole 40 mg for 5 days had no effect on exposure [7] | No restriction in the label [7] |
| Palbociclib (tablets) | Rabeprazole under fasted conditions had no effect on absorption; no effect is expected from H2 antagonists or antacids either [8] | No restriction in the label [8] |
If a patient on erlotinib or dasatinib needs acid suppression, consider an antacid first, timed as the label says, and for erlotinib an H2 antagonist with exact timing [5, 6]. In an EGFR-positive patient who needs a long-term PPI, osimertinib absorption did not change with omeprazole [7]. Treatment of these patients is covered in treatment of EGFR-mutant lung cancer.
Capecitabine–warfarin interaction and other drugs that raise the INR
The capecitabine label carries a boxed warning on altered coagulation and bleeding, including death, with concomitant vitamin K antagonists such as warfarin. Clinically significant rises in PT and INR in patients on stable warfarin doses occurred from several days to several months after starting capecitabine and, in a few cases, up to one month after stopping it, in patients with and without liver metastases [10].
In 4 patients, capecitabine 1,250 mg/m2 twice daily increased the AUC of S-warfarin by 57%, decreased its clearance by 37% and raised the maximum INR by 91%. Label recommendation: monitor the INR more frequently and adjust the warfarin dose [10].
- The same label: monitor phenytoin levels; do not give allopurinol at the same time (lower levels of the active metabolites); leucovorin and folic acid increase fluorouracil toxicity [10].
- Erlotinib: raised INR and bleeding, sometimes fatal, with coumarin anticoagulants; monitor the PT or INR regularly [6].
- Venetoclax: raised the Cmax and AUC of warfarin by 18% to 28%; monitor the INR more often [3].
DPYD testing before capecitabine is covered in the DPYD testing lesson, and the choice of anticoagulant in cancer patients in the cancer-associated thrombosis lesson.
Methotrexate interactions with PPIs, NSAIDs and antibiotics
Methotrexate label: the drugs below raise methotrexate levels and increase the risk of severe adverse reactions; if concomitant use cannot be avoided, monitor the patient closely for methotrexate toxicity [11]:
- Proton pump inhibitors (omeprazole, pantoprazole and similar drugs)
- Aspirin and non-steroidal anti-inflammatory drugs; unexpectedly severe and fatal gastrointestinal toxicity, mainly with high-dose methotrexate
- Penicillins and sulfonamide antibiotics (such as co-trimoxazole)
- Probenecid and antifolates (dapsone, pemetrexed, pyrimethamine)
- Highly protein-bound drugs (oral anticoagulants, phenytoin, salicylates, sulfonylureas, tetracyclines) and drugs that are toxic to the liver or kidneys
Also avoid nitrous oxide anaesthesia in patients on methotrexate, and note that folic acid reduces the effect of methotrexate in cancer [11]. Dasatinib delays the clearance of high-dose methotrexate (more than 500 mg/m2) [5].
What drugs interact with apixaban?
Apixaban is a substrate of CYP3A4 and P-gp [12]:
- Combined P-gp and strong CYP3A4 inhibitors (ketoconazole, itraconazole, ritonavir): at 5 or 10 mg twice daily, reduce the dose by 50%; at 2.5 mg twice daily, avoid concomitant use. Clarithromycin, despite having these properties, needs no dose change [12].
- Combined P-gp and strong CYP3A4 inducers (rifampicin, carbamazepine, phenytoin): avoid concomitant use; the lower exposure raises the risk of stroke and thrombosis [12].
- Drugs affecting haemostasis: aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytics, SSRIs, SNRIs and NSAIDs increase the risk of bleeding [12].
- Anticancer drugs: enzalutamide and apalutamide are strong CYP3A inducers [1]; check their combination with apixaban in an interaction resource. Adding an antiplatelet or anticoagulant to ibrutinib increases the risk of major haemorrhage: in 2,838 patients, 3.1% without antiplatelet or anticoagulant therapy, 4.4% when an antiplatelet is added and 6.1% when an anticoagulant is added [4].
The choice between low-molecular-weight heparin and oral anticoagulants in cancer patients is covered in the cancer-associated thrombosis lesson.
QT prolongation: ribociclib, osimertinib and co-medications
- Ribociclib: prolongs the QT interval in a concentration-dependent way. ECG before starting, at about day 14 of the first cycle and as clinically indicated; electrolytes at the start of each cycle for 6 cycles. Avoid QT-prolonging drugs (such as antiarrhythmics) and strong CYP3A inhibitors; ribociclib is not indicated for use with tamoxifen. In advanced disease (600 mg) 1.4% and in early breast cancer (400 mg) 0.3% of patients had a QTcF above 500 ms [9].
- Osimertinib: of 1,813 patients on monotherapy, 1.1% had a QTc above 500 ms and 4.3% an increase of more than 60 ms; in congenital long QT syndrome, heart failure, electrolyte disorders or with QT-prolonging drugs, check ECGs and electrolytes periodically [7].
Calculate the QTc with the QTc calculator; cardiac monitoring is covered in the cardio-oncology monitoring lesson.
How to check for drug interactions
Checking interactions for every oral anticancer prescription
- 1
A complete medication list
At the start of treatment and at every visit, ask about all medicines: prescribed, over-the-counter, supplements, drops and medicines prescribed by other doctors. The number of comorbidities and of over-the-counter drugs were determinants of the need for an intervention [2].
- 2
- 3
Database and pharmacist
Check the medication list with drug interaction software or a database, and review important findings with a clinical pharmacist or clinical pharmacologist; structured screening before and during treatment is recommended [2].
- 4
- 5
A plan for when the co-medication stops
Return to the previous dose: venetoclax 2 to 3 days after the inhibitor is stopped [3], palbociclib after 3 to 5 half-lives of the inhibitor [8], dasatinib about 1 week after the inhibitor is stopped [5] and osimertinib 3 weeks after the inducer is stopped [7].
- 6
Patient education
Tell the patient to call before starting any new medicine, even a short course of an antibiotic or antifungal; for example, ibrutinib is interrupted during short-term use (7 days or less) of a strong CYP3A inhibitor [4]. Point them to the patient section of this page and to the page on foods during chemotherapy.
- Venetoclax with posaconazole: in CLL contraindicated during the ramp-up, then 70 mg; in AML 10, 20, 50 and 70 mg [3].
- Ibrutinib: moderate inhibitor 280 mg; voriconazole 140 mg; high-dose posaconazole 70 mg [4].
- Dasatinib 100 mg with a strong inhibitor: 20 mg; no PPIs or H2 antagonists; antacid with a 2-hour gap [5].
- Osimertinib: exposure did not change meaningfully with omeprazole or itraconazole; 160 mg with rifampicin [7].
- With a strong CYP3A inhibitor: palbociclib 75 mg and ribociclib 400 mg in advanced disease [8, 9].
- Capecitabine and warfarin: boxed warning; monitor the INR frequently during treatment and after stopping (INR rises have been seen up to one month after stopping) [10].
- Apixaban with ketoconazole, itraconazole or ritonavir: half the dose (if 5 or 10 mg twice daily); with rifampicin, carbamazepine or phenytoin: do not use [12].
Self-assessment questions
Venetoclax–posaconazole interaction: a 72-year-old woman with newly diagnosed AML is starting azacitidine and venetoclax and needs antifungal prophylaxis with posaconazole delayed-release tablets 300 mg daily. What is the venetoclax dose?
Day 1: 10 mg, day 2: 20 mg, day 3: 50 mg and day 4: 70 mg, then 70 mg daily; if posaconazole is stopped, return to the previous dose 2 to 3 days later [3]. Antifungal prophylaxis is covered in the infection prevention lesson.
A 68-year-old man with CLL on ibrutinib 420 mg develops pneumonia and is prescribed a 7-day course of clarithromycin. What do you do?
Dasatinib and PPIs: a patient with CML on dasatinib 100 mg asks for omeprazole for heartburn. What do you advise?
Osimertinib and PPI interaction: a patient with EGFR-positive lung cancer on osimertinib 80 mg takes pantoprazole for reflux and needs rifampicin for tuberculosis. What needs to change?
Omeprazole had no effect on osimertinib exposure and the label sets no restriction on acid suppressants, so pantoprazole can be continued. Rifampicin lowered the AUC of osimertinib by 78%; avoid it, and if it is unavoidable give osimertinib 160 mg daily and return to 80 mg 3 weeks after rifampicin is stopped [7].
Capecitabine–warfarin interaction: a 70-year-old man with atrial fibrillation on warfarin with a stable INR starts capecitabine for colorectal cancer. What matters most?
Monitor the INR frequently and adjust the warfarin dose; clinically significant INR rises have been reported from several days to several months after starting and, in a few cases, up to one month after stopping capecitabine [10].
A patient on apixaban 5 mg twice daily for cancer-associated thrombosis needs itraconazole. What happens to the apixaban dose?
Methotrexate and PPI interaction: a patient with acute lymphoblastic leukaemia is taking omeprazole and naproxen before high-dose methotrexate. What do you do?
PPIs and NSAIDs raise methotrexate levels; stop them before methotrexate if possible, and if not, monitor the patient closely for methotrexate toxicity. NSAIDs have caused unexpectedly severe and fatal gastrointestinal toxicity, especially with high-dose methotrexate [11].
A 45-year-old premenopausal woman with advanced hormone receptor-positive breast cancer: can ribociclib be given with tamoxifen?
No; ribociclib is not indicated for use with tamoxifen, because the combination prolongs the QT interval further [9]. Endocrine partners for CDK4/6 inhibitors are covered in treatment of hormone receptor-positive breast cancer.
Related cancer types
Treatment regimens (physicians)
Physician tools and lessons
References
12 referencesShow all referencesClose the reference list
Numbers in the text, such as [1], refer to these sources. Sources with a “Study card” button are summarised in the site’s evidence library.
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This page is based on reputable scientific sources and was last updated on 28 October 2026. The content of this website is for educational and informational purposes only and does not replace consultation, diagnosis or treatment by a specialist physician. Consult your treating physician about any treatment decision.
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