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Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
afatinib | - | rifampicin |
Recommendations on how DDIs can be managed
Reduce afatinib dose to 10 mg/day if co-administration with ketoconazole is not tolerated; or administer ketoconazole in staggered doses, preferably 6 or 12 hours apart from afatinib
For patients requiring chronic rifampicin therapy, increase the daily dose of afitinib by 10 mg based on tolerability
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Axitinibe | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
If use of potent CYP3A4/5 inhibitors is unavoidable, reduce the dose of axitinib by approximately half based on tolerability
If the use of strong CYP3A4/5 inducers is unavoidable, a gradual increase in the dose of axitinib is recommended, with patients carefully monitored for toxicity
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Go slow | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
Consider discontinuing or reducing bosutinib dose when co-administration with a strong CYP3A inhibitor is required
Avoid co-administration of bosutinib with strong CYP3A inducers; Increasing bosutinib dose is unlikely to sufficiently compensate for the loss of exposure
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Cabozantinib | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
Avoid co-administration of cabozantinib with CYP3A4 inhibitors/inducers
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Ceritinib | Virostatics (from B. Ritonavir), Macrolide Antibiotics (from B. Telithromycin), Antifungals (from B. Ketoconazole) and Nefazodone | Rifampicin, Carbamaze-Kiefer, Phenytoin, Rifampicin, Johanniskraut |
Recommendations on how DDIs can be managed
Avoid concomitant use of strong CYP3A4 inhibitors. If unavoidable, reduce the dose by about one-third (rounded to the nearest 150 mg dosage).
After stopping a strong CYP3A4 inhibitor, resume the dose taken before starting treatment with the strong CYP3A4 inhibitor
Avoid concomitant use of strong CYP3A inducers
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
crizotinib | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
If concomitant use with a CYP3A4 inhibitor is unavoidable, extreme caution should be exercised, the dose of crizotinib reduced and toxicity monitored.
If concomitant use with a CYP3A4 inducer is unavoidable, gradually increase the dose of crizotinib and monitor toxicity to achieve optimal efficacy
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
dabrafenibe | ketoconazole | - |
Recommendations on how DDIs can be managed
If co-administration of dabrafenib with strong CYP3A4 inhibitors/inducers is unavoidable, monitor patients closely for adverse reactions (for strong inhibitors) or loss of efficacy (for strong inducers).
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
dasatinibe | - | rifampicin |
Recommendations on how DDIs can be managed
If concomitant use is unavoidable, monitor patients closely for toxicity and consider reducing dasatinib dose (from 100 to 20 mg/day or 140 to 40 mg/day) with strong CYP3A4 inhibitors or increasing dasatinib dose with CYP3A4 inducers
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Erlotinibe | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
Reduce erlotinib dose in 50 mg increments if severe reactions occur with concomitant use of strong CYP3A4 inhibitors
If concomitant use with CYP3A4 inducers is unavoidable, increase the dose of erlotinib in 50 mg increments at 2-week intervals to a maximum of 450 mg
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
gefitinibe | Itraconazole | rifampicin |
Recommendations on how DDIs can be managed
Monitor patients closely for adverse reactions when gefitinib is co-administered with a CYP3A4 inhibitor
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Ibrutinibe | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
When co-administered with strong CYP3A4 inhibitors, the ibrutinib dose should be reduced to 140 mg once daily or withheld for up to 7 days
If it is necessary to use a strong CYP3A4 inducer, patients should be closely monitored for lack of efficacy
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Ideally | ketoconazole | Rifampin, Phenytoin, John's Wort, Carbamazepine |
Recommendations on how DDIs can be managed
Avoid co-administration with strong CYP3A4 inducers
Watch for signs of toxicity when patients are taking potent CYP3A inhibitors
See the idelasib summary of product characteristics and prescribing information for a variety of products that are CYP3A4 substrates
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Imatinibe | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
Consider decreasing imatinib dose to 300 mg/24 hours when co-administered with potent CYP3A4 inhibitors
If concomitant use of imatinib and a strong CYP3A4 inducer is required, the dose of imatinib should be increased to 600-700 mg/24 hours
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Lapatinibe | ketoconazole | carbamazepine |
Recommendations on how DDIs can be managed
If concomitant use of a strong CYP3A4 inhibitor is unavoidable, the dose of lapatinib should be reduced to 500 mg/day
If concomitant use of a strong CYP3A4 inducer is unavoidable, the dose of lapatinib should be titrated gradually from 1250 mg/day to 4500 mg/day (indication for HER2-positive metastatic breast cancer) or from 1500 mg/day to 5500 mg/day (hormone receptor positive, indication of HER2 positive breast cancer) based on tolerability
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Lenvatinibe | ketoconazole | Rifamypicin |
Recommendations on how DDIs can be managed
No dose adjustments are required when co-administered with CYP3A4 inhibitors and inducers
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Nilotinib | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
If administration of a strong CYP3A4 inhibitor is required, it is recommended to withhold nilotinib therapy if possible, otherwise close monitoring for QT interval prolongation is indicated
In patients for whom CYP3A4 inducers are indicated, alternative agents with lower enzyme induction potential should be selected.
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
you are sad | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
With concomitant use of CYP3A4 inhibitors, patients should be closely monitored for tolerability and adverse reactions should be managed with interruption, dose reduction (to 100 mg twice daily) or discontinuation of nintedanib
Avoid co-administration of nintedanib with CYP3A4 inducers
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
not yet | ketoconazole | - |
Recommendations on how DDIs can be managed
If concomitant use of strong CYP3A4 inhibitors is required, reduce the pazopanib dose to 400 mg
In patients for whom CYP3A4 inducers are indicated, alternative agents with lower enzyme induction potential should be selected.
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Ponatinib | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
If co-administration with a strong CYP3A4 inhibitor is warranted, reduce starting dose of ponatinib to 30 mg once daily
In patients for whom CYP3A4 inducers are indicated, alternative agents with lower enzyme induction potential should be selected.
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
regorafenibe | - | - |
Recommendations on how DDIs can be managed
If concomitant use with a strong CYP3A4 inhibitor cannot be avoided, the toxicity of regorafenib should be monitored; Dose adjustments are strongly recommended.
If co-administration with a strong CYP3A4 inducer cannot be avoided, gradually increase the regorafenib dose and monitor toxicity
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Ruxolitinib | ketoconazole | rifampicin |
Recommendations on how DDIs can be managed
If co-administration with a strong CYP3A4 inhibitor cannot be avoided, the dose of ruxolitinib should be reduced by approximately 50% for twice-daily administration; Interruption or discontinuation of ruxolitinib should also be considered.
If co-administration with a strong CYP3A4 inducer cannot be avoided, the dose of ruxolitinib should be titrated (increased to a maximum of 5 mg twice daily) based on safety and efficacy.
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
sorafenibe | - | rifampicin |
Recommendations on how DDIs can be managed
Consider increasing sorafenib dose to 1000 mg/24 hours when co-administered with rifampicin
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Sunitinibe | - | - |
Recommendations on how DDIs can be managed
If co-administration with a strong CYP3A4 inhibitor cannot be avoided, consider reducing the sunitinib dose to a minimum of 37.5 mg per day for GIST and mRCC or 25 mg per day for pNET, based on careful monitoring of tolerability
If co-administration with a CYP3A4 inducer is required, consideration should be given to escalating the sunitinib dose by 12.5 mg increments (up to 87.5 mg/day for GIST and mRCC or 62.5 mg/day for pNET). should be considered based on careful monitoring of tolerability
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Trametinib | - | - |
Recommendations on how DDIs can be managed
Trametinib is not a substrate for CYP or P-gp enzymes. Trametinib is deacetylated via hydrolytic enzymes, which are generally not associated with a risk of interaction
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Vandertanibe | rifampicin |
Recommendations on how DDIs can be managed
Vandetanib can be co-administered with CYP3A4 inhibitors if used with caution
Co-administration of vandetanib with strong CYP3A4 inducers is not recommended
Kinase Inhibitor | CYP3A4 Inhibitor Drug(s) | CYP3A4-inducing drug(s) |
|---|---|---|
Vemurafenib | - | - |
Recommendations on how DDIs can be managed
Caution should be exercised when administering vemurafenib concomitantly with CYP3A4 inhibitors/inducers, as no data are currently available on this DDI
For more information on the most commonly used kinase inhibitors, click on individual compounds below to learn more about drug interactions associated with CYP3A4 inhibitors/inducers.
- Erlotinibe
- Imatinibe
- regorafenibe
- sorafenibe
- Sunitinibe
- Vandertanibe
- Vemurafenib
references
- Management of food and medicine. 2015(last accessed July 2015)
- European Medicines Agency. 2015(last accessed July 2015)